Anti-CD3 antibodies and methods of use

ABSTRACT

The invention provides anti-cluster of differentiation 3 (CD3) antibodies and methods of using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 14/574,132, filed on Dec. 17, 2014, which claims benefit of thefiling date of U.S. Provisional Application No. 62/091,441, filed onDec. 12, 2014; U.S. Provisional Application No. 62/053,582, filed onSep. 22, 2014; U.S. Provisional Application No. 62/026,594, filed onJul. 18, 2014; U.S. Provisional Application No. 61/949,950, filed onMar. 7, 2014; and U.S. Provisional Application No. 61/917,346, filed onDec. 17, 2013.

SEQUENCE LISTING

The present application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Feb. 12, 2020, isnamed 50474-0520010_Sequence_Listing_2.12.20_ST25 and is 286,219 bytesin size.

FIELD OF THE INVENTION

The present invention relates to anti-cluster of differentiation 3 (CD3)antibodies and methods of using the same.

BACKGROUND

Cell proliferative disorders, such as cancer, are characterized by theuncontrolled growth of cell subpopulations. They are the leading causeof death in the developed world and the second leading cause of death indeveloping countries, with over 12 million new cancer cases diagnosedand 7 million cancer deaths occurring each year. The National CancerInstitute estimates that greater than half a million Americans will dieof cancer in 2013, accounting for nearly one out of every four deaths inthe country. As the elderly population has grown, the incidence ofcancer has concurrently risen, as the probability of developing canceris more than two-fold higher after the age of seventy. Cancer care thusrepresents a significant and ever-increasing societal burden.

Longstanding approaches to cancer treatment include chemotherapy,radiation therapy, and surgery to remove solid tumors. Recently,bispecific antibody-based immunotherapies have been developed. Suchbispecific antibodies are capable of simultaneously binding cell surfaceantigens on cytotoxic cells and tumor cells, with the intent that thebound cytotoxic cell will destroy the bound tumor cell. Existingbispecific antibodies currently undergoing clinical trials for treatingcancer are limited by their short half-lives and/or variable efficacy.Thus, there is an unmet need in the field for the development ofeffective bispecific antibodies for use in cancer treatment.

SUMMARY

The present invention relates to anti-cluster of differentiation 3 (CD3)antibodies and methods of using the same.

In one aspect, the invention features an anti-CD3 antibody, wherein theanti-CD3 antibody comprises a binding domain comprising the followingsix hypervariable regions (HVRs): (a) an HVR-H1 comprising the aminoacid sequence of SEQ ID NO: 1; (b) an HVR-H2 comprising the amino acidsequence of SEQ ID NO: 2; (c) an HVR-H3 comprising the amino acidsequence of SEQ ID NO: 3; (d) an HVR-L1 comprising the amino acidsequence of SEQ ID NO: 4; (e) an HVR-L2 comprising the amino acidsequence of SEQ ID NO: 5; and (f) an HVR-L3 comprising the amino acidsequence of SEQ ID NO: 6. In some embodiments, the binding domaincomprises (a) a heavy chain variable (VH) domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 184; (b) a light chain variable (VL) domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 185; or (c) a VH domain as in(a) and a VL domain as in (b). In some embodiments, the VH domaincomprises the amino acid sequence of SEQ ID NO: 184. In someembodiments, the VL domain comprises the amino acid sequence of SEQ IDNO: 185. In some embodiments, the binding domain comprises (a) a heavychain variable (VH) domain comprising an amino acid sequence having atleast 95% sequence identity to the amino acid sequence of SEQ ID NO:186; (b) a light chain variable (VL) domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 187; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 186. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 187.

In one aspect, the invention features an anti-CD3 antibody, wherein theanti-CD3 antibody comprises a binding domain comprising the followingsix HVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO:7; (b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c)an HVR-H3 comprising the amino acid sequence of X₁X₂YSX₃X₄X₅FDY, whereinX₁ is selected from the group consisting of D, T, and S; X₂ is selectedfrom the group consisting of G, A, and S; X₃ is R or N; X₄ is Y or A;and X₅ is Y or A (SEQ ID NO: 181); (d) an HVR-L1 comprising the aminoacid sequence of SEQ ID NO: 10; (e) an HVR-L2 comprising the amino acidsequence of SEQ ID NO: 11; and (f) an HVR-L3 comprising the amino acidsequence of X₁X₂SX₃X₄LRT, wherein X₁ is K or T; X₂ is Q or A; X₃ is F orA; and X₄ is I or A (SEQ ID NO: 182). In some embodiments, the bindingdomain comprises the following six HVRs: (a) an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 7; (b) an HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 8; (c) an HVR-H3 comprising the amino acidsequence of SEQ ID NO: 9; (d) an HVR-L1 comprising the amino acidsequence of SEQ ID NO: 10; (e) an HVR-L2 comprising the amino acidsequence of SEQ ID NO: 11; and (f) an HVR-L3 comprising the amino acidsequence of SEQ ID NO: 12. In some embodiments, the binding domaincomprises (a) a VH domain comprising an amino acid sequence having atleast 95% sequence identity to the amino acid sequence of SEQ ID NO:188; (b) a VL domain comprising an amino acid sequence having at least95% sequence identity to the amino acid sequence of SEQ ID NO: 189; or(c) a VH domain as in (a) and a VL domain as in (b). In someembodiments, the VH domain comprises the amino acid sequence of SEQ IDNO: 188. In some embodiments, the VL domain comprises the amino acidsequence of SEQ ID NO: 189.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 190; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 191; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 190. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 191.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) an HVR-L1comprising the amino acid sequence of SEQ ID NO: 10; (e) an HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3comprising the amino acid sequence of SEQ ID NO: 14. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 192; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 193; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 192. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 193.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) an HVR-L1comprising the amino acid sequence of SEQ ID NO: 10; (e) an HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3comprising the amino acid sequence of SEQ ID NO: 15. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 194; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 195; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 194. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 195.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) an HVR-L1comprising the amino acid sequence of SEQ ID NO: 10; (e) an HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) an HVR-L3comprising the amino acid sequence of SEQ ID NO: 16. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 196; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 197; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 196. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 197.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 198; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 199; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 198. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 199.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 200; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 201; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 200. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 201.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 202; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 203; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 202. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 203.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 204; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 205; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 204. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 205.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 206; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 207; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 206. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 207.

In some aspects, the invention features an anti-CD3 antibody comprisinga binding domain comprising: (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 188 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 189; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 190 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 191; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 192 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 193; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 194 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 195; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 196 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 197; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 198 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 199; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 200 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 201; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 202 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 203; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 204 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 205; or (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 206 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 207.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 23; (b) an HVR-H2 comprising the amino acid sequence ofLINPYKGVX₁TYX₂X₃X₄X₅KX₆, wherein X₁ is S or T; X₂ is N or A; X₃ is Q orD; X₄ is K or S; X₅ is F or V; and X₆ is D or G (SEQ ID NO: 183); (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In someembodiments, the binding domain comprises the following six HVRs: (a) anHVR-H1 comprising the amino acid sequence of SEQ ID NO: 23; (b) anHVR-H2 comprising the amino acid sequence of SEQ ID NO: 24; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 208; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 209; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 208. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 209.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29; (c)an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 210; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 211; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 210. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 211.

In other embodiments, the binding domain comprises the following sixHVRs: (a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 23;(b) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 30; (c)an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 28. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 212; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 213; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 212. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 213.

In some aspects, the invention features an anti-CD3 antibody comprisinga binding domain comprising: (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 208 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 209; (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 210 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 211; or (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 212 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 213.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 31; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 32; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 33; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 214; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 215; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 214. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 215. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 216; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 217; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 216. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 217.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 214 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 215, or (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 216 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 217.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 37; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 38; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 39; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 218; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 219; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 218. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 219. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 220; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 221; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 220. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 221.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 218 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 219, or (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 220 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 221.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 43; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 44; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 45; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 222; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 223; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 222. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 223. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 224; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 225; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 224. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 225. In some embodiments, thebinding domain comprises (a) a VH domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 226; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 227; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 226. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 227.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 222 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 223; (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 224 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 225; (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 226 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 227.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 49; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 50; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 51; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 228; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 229; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 228. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 229. In someembodiments, the binding domain comprises (a) a VH domain comprising anamino acid sequence having at least 95% sequence identity to the aminoacid sequence of SEQ ID NO: 230; (b) a VL domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 231; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 230. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 231.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 228 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 229, or (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 230 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 231.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 55; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 56; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 57; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 232; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 233; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 232. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 233.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 232 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 233.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 61; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 62; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 63; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 234; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 235; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 234. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 235.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 234 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 235.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 67; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 68; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 69; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 236; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 237; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 236. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 237.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 236 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 237.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 73; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 74; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 75; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 238; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 239; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 238. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 239.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 238 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 239.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 79; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 80; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 81; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 240; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 241; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 240. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 241.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 240 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 241.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 85; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 86; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 87; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 242; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 243; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 242. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 243.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 242 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 243.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 91; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 92; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 93; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 244; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 245; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 244. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 245.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 244 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 245.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 97; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 98; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 99; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 246; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 247; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 246. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 247.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 246 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 247.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 103; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 104; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 105; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:106; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 107;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 108.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 248; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 249; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 248. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 249.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 248 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 249.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 109; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 110; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 111; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:112; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 113;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 114.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 250; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 251; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 250. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 251.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 250 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 251.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 115; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 116; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 117; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:118; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 252; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 253; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 252. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 253.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 252 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 253.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 121; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 122; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 123; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:124; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 125;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 126.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 254; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 255; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 254. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 255.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 254 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 255.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 127; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 128; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 129; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:130; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 131;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 132.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 256; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 257; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 256. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 257.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 256 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 257.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 133; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 134; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 135; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:136; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 258; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 259; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 258. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 259.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 258 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 259.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 139; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 140; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 141; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:142; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 260; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 261; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 260. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 261.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 260 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 261.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 145; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 146; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 147; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:148; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 149;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 150.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 262; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 263; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 262. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 263.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 262 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 263.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 151; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 152; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 153; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:154; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 155;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 156.In some embodiments, the binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 264; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 265; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 264. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 265.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a binding domain comprising: (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 264 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 265.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody binds to an epitope on CD3 comprising amino acidresidue Glu6 of CD3. In certain aspects, the invention features ananti-CD3 antibody, wherein the epitope further comprises one or moreadditional amino acid residues selected from the group consisting ofGln1, Asp2, and Met7 of CD3. In a further aspect, the invention featuresan anti-CD3 antibody, wherein the epitope comprises amino acid residuesGln1, Asp2, and Glu6 of CD3. In certain aspects, the invention featuresan anti-CD3 antibody, wherein the epitope comprises amino acid residuesGln1, Asp2, Glu6, and Met7 of CD3. In another aspect, the inventionfeatures an anti-CD3 antibody, wherein the epitope does not compriseamino acid residue Glu5 of CD3. In a further aspect, the inventionfeatures an anti-CD3 antibody, wherein the epitope does not compriseamino acid residues Gly3 and Glu5 of CD3. In certain aspects, theinvention features an anti-CD3 antibody, wherein the epitope consists ofamino acid residues Gln1, Asp2, Glu6, and Met7 of CD3.

In related aspects, the invention features an anti-CD3 antibody thatbinds such an epitope and that is a multispecific antibody. In someembodiments, the multispecific antibody is a bispecific antibody. Insome embodiments, the bispecific antibody comprises a second bindingdomain that binds to a second biological molecule, wherein the secondbiological molecule is a cell surface antigen. In some embodiments, thecell surface antigen is a tumor antigen. In some embodiments, the tumorantigen is selected from the group consisting of CD20; FcRH5 (FcReceptor-like 5); HER2; LYPD1; Ly6G6D (lymphocyte antigen 6 complex,locus G61); Ly6-D, MEGT1); PMEL17 (silver homolog; SILV; D12S53E;PMEL17; (SI); (SIL); ME20; gp100); Ly6E (lymphocyte antigen 6 complex,locus E; Ly67, RIG-E, SCA-2, TSA-1); CD19; CD33; CD22 (B-cell receptorCD22-B isoform); CD79a (CD79A, CD79a, immunoglobulin-associated alpha;BMPR1B (bone morphogenetic protein receptor-type IB); CD79b (CD79B,CD79β, 1 Gb (immunoglobulin-associated beta), B29); EDAR (EctodysplasinA Receptor); GFRA1 (GDNF-Ra1); MRP4 (Multidrug Resistance Protein 4);RET; STEAP1 (six transmembrane epithelial antigen of prostate); TENB2(putative transmembrane proteoglycan); E16 (LAT1, SLC7A5); 0772P (CA125,MUC16); MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor,mesothelin); Napi2b (NAPI-2B, NPTIIb, SLC34A2, solute carrier family 34(sodium phosphate), member 2, type II sodium-dependent phosphatetransporter 3b); Sema 5b; PSCA hIg (2700050C12Rik, C530008016Rik, RIKENcDNA 2700050C12, RIKEN cDNA 2700050C12 gene); ETBR (Endothelin type Breceptor); MSG783 (RNF124, hypothetical protein FLJ20315); STEAP2; TrpM4(BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cationchannel, subfamily M, member 4); CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1,teratocarcinoma-derived growth factor); CD21 (CR2 (Complement receptor2) or C3DR (C3d/Epstein Barr virus receptor) or Hs.73792); FcRH2 (IFGP4,IRTA4, SPAP1A (SH2 domain containing phosphatase anchor protein 1a),SPAP1B, SPAP1C); NCA; MDP; IL20Rα; Brevican; EphB2R; ASLG659; PSCA;GEDA; BAFF-R (B cell-activating factor receptor, BLyS receptor 3, BR3);CXCR5 (Burkitt's lymphoma receptor 1; HLA-DOB (Beta subunit of MHC classII molecule); P2X5 (Purinergic receptor P2X ligand-gated ion channel 5;CD72 (B-cell differentiation antigen CD72, Lyb-2); LY64 (Lymphocyteantigen 64 (RP105), type I membrane protein of the leucine rich repeat(LRR) family); FcRH1 (Fc receptor-like protein 1); IRTA2 (Immunoglobulinsuperfamily receptor translocation associated 2); TMEFF1; TMEM46 (shisahomolog 2 (Xenopus laevis); SHISA2); LGR5 (leucine-richrepeat-containing G protein-coupled receptor 5; GPR49, GPR67); LY6K(lymphocyte antigen 6 complex, locus K; LY6K; HSJ001348; FLJ35226);GPR19 (G protein-coupled receptor 19; Mm 4787); GPR54 (KISS1 receptor;KISS1R; GPR54; HOT7T175; AXOR12); ASPHD1 (aspartate beta-hydroxylasedomain containing 1; LOC253982); Tyrosinase (TYR; OCAIA; OCA1A;tyrosinase; SHEP3); TMEM118 (ring finger protein, transmembrane 2;RNFT2; FLJ14627); GPR172A (G protein-coupled receptor 172A; GPCR41;FLJ11856; D15Ertd747e); GPC3 (Glypican 3); CLL1 (C-Type Lectin-likemolecule 1); B7-H4 (B7x; B7S1); RNF43 (Ring finger protein 43); CD70;CXORF61 (Chromosome X open reading frame 61); HAVCR1; Epiregulin;Amphiregulin; EGFR; EGFR-L858R; EGFR-L861Q; EGFR-G719A; EGFR-G719S;EGFR-G719C; EGFR-T790M; EGFR-S7681; adipophilin; AIM-2; ALDH1A1;alpha-actinin-4; alpha-foetoprotein; ARTC1; B-RAF; BAGE-1; BCLX (L);BCR-ABL fusion protein (b3a2); beta-catenin; BING-4; CALCA; CASP-5;CASP-8; CD45; Cdc27; CDK4; CDKN2A; CEA; CLPP; COA-1; CPSF; Cw6; cyclinD1; Cyclin-A1; dek-can fusion protein; DKK1; DR1; DR13; EFTUD2;Elongation factor 2; ENAH (hMena); EpCAM; EphA3; ETV6-AML1 fusionprotein; EZH2; FLT3-ITD; FN1; G250; MN; CAIX; GAGE-1;2;8;GAGE-3;4;5;6;7; glypican-3; GnTVf; gp100/Pmel17; GPNMB; HERV-K-MEL;hsp70-2; IDO1; IGF2B3; IL13Ralpha2; Intestinal carboxyl esterase; K-ras;Kallikrein 4; KIF20A; KK-LC-1; KM-HN-1; LAGE-1;LDLR-fucosyltransferaseASfusion protein; Lengsin; M-CSF; MAGE-A1;MAGE-A10; MAGE-A12; MAGE-A2; MAGE-A3; MAGE-A4; MAGE-A6; MAGE-A9;MAGE-C1; MAGE-C2; mammaglobin-A; MART2; MCSP; mdm-2; ME1;Melan-A/MART-1; Meloe; MMP-2; MMP-7; MUC1; MUC5AC; mucin; MUM-1f; MUM-2;MUM-3; Myosin class I; N-ras; NA88-A; neo-PAP; NFYC; NY-BR-1;NY-ESO-1/LAGE-2; OA1; OGT; OS-9; p53; PAP; PAX5; PBF; pml-RARalphafusion protein; PRAME; PRDX5; PSMA; PTPRK; RAB38/NY-MEL-1; RAGE-1;RBAF600; RGS5; RhoC; RNF43; RU2AS; SAGE; secernin 1; SIRT2; SNRPD1;SOX10; Sp17; SSX-2; SSX-4; STEAP1; survivin; SYT-SSX1 or -SSX2 fusionprotein; TAG-1; TAG-2; Telomerase; TGF-betaRII; TRAG-3; Triosephosphateisomerase; TRP-1/gp75; TRP-2; TRP2-INT2; tyrosinase; VEGF; WT1; XAGE-1b/GAGED2a; and SLC53SLC35D3. In some embodiments, the tumor antigen isselected from the group consisting of CD20, FcRH5, HER2, LYPD1, LY6G6D,PMEL17, LY6E, CD19, CD33, CD22, CD79A, CD79B, EDAR, GFRA1, MRP4, RET,Steap1, and TenB2. In preferred embodiments, the tumor antigen isselected from the group consisting of CD20, HER2, FcRH5, and LYPD1.

In some embodiments, the binding domain of any one of the precedinganti-CD3 antibodies binds to a human CD3 polypeptide or a cynomolgusmonkey (cyno) CD3 polypeptide. In some embodiments, the human CD3polypeptide or the cyno CD3 polypeptide is a human CD3ε polypeptide or acyno CD3ε polypeptide, respectively. In some embodiments, the human CD3polypeptide or the cyno CD3 polypeptide is a human CD3γ polypeptide or acyno CD3γ polypeptide, respectively.

In some embodiments, any one of the preceding anti-CD3 antibodies bindsthe human CD3ε polypeptide with a Kd of 250 nM or lower. In someembodiments, the anti-CD3 antibody binds the human CD3ε polypeptide witha Kd of 100 nM or lower. In some embodiments, the anti-CD3 antibodybinds the human CD3ε polypeptide with a Kd of 15 nM or lower. In someembodiments, the anti-CD3 antibody binds the human CD3ε polypeptide witha Kd of 10 nM or lower. In some embodiments, the anti-CD3 antibody bindsthe human CD3ε polypeptide with a Kd of 5 nM or lower.

In some embodiments, any one of the preceding anti-CD3 antibodies maycomprise an aglycosylation site mutation. In some embodiments, theaglycosylation site mutation is a substitution mutation. In someembodiments, the substitution mutation is at amino acid residue N297,L234, L235, and/or D265 (EU numbering). In some embodiments, thesubstitution mutation is selected from the group consisting of N297G,N297A, L234A, L235A, and D265A. In some embodiments, the substitutionmutation is an N297G mutation. In some embodiments, the aglycosylationsite mutation reduces effector function of the anti-CD3 antibody. Insome embodiments, the aglycosylation site mutation reduces effectorfunction of the anti-CD3 antibody. In some embodiments, an anti-CD3antibody comprises a substitution mutation in the Fc region that reduceseffector function.

In some embodiments, any one of the preceding anti-CD3 antibodies can bemonoclonal, human, humanized, or chimeric. In some embodiments, any oneof the preceding anti-CD3 antibodies can be an antibody fragment thatbinds CD3. In some embodiments, the antibody fragment is selected fromthe group consisting of Fab, Fab′-SH, Fv, scFv, and (Fab′)₂ fragments.In other embodiments, the anti-CD3 antibody is a full-length antibody.In some embodiments, the anti-CD3 antibody is an IgG antibody (e.g., anIgG1, IgG2, or IgG3 antibody). In some embodiments, the anti-CD3antibody is a monospecific antibody. In some embodiments, the anti-CD3antibody is a Bispecific T-Cell Engager (BiTE®) antibody).

In some embodiments, the anti-CD3 antibody is a multispecific antibody.In some embodiments, the multispecific antibody is a bispecificantibody. In some embodiments, the bispecific antibody comprises asecond binding domain that binds to a second biological molecule,wherein the second biological molecule is a cell surface antigen. Insome embodiments, the cell surface antigen is a tumor antigen. In someembodiments, the tumor antigen is selected from the group consisting ofCD20; FcRH5 (Fc Receptor-like 5); HER2; LYPD1; Ly6G6D (lymphocyteantigen 6 complex, locus G61); Ly6-D, MEGT1); PMEL17 (silver homolog;SILV; D12S53E; PMEL17; (SI); (SIL); ME20; gp100); Ly6E (lymphocyteantigen 6 complex, locus E; Ly67, RIG-E, SCA-2, TSA-1); CD19; CD33; CD22(B-cell receptor CD22-B isoform); CD79a (CD79A, CD79a,immunoglobulin-associated alpha; BMPR1B (bone morphogenetic proteinreceptor-type IB); CD79b (CD79B, CD79β, 1 Gb (immunoglobulin-associatedbeta), B29); EDAR (Ectodysplasin A Receptor); GFRA1 (GDNF-Ra1); MRP4(Multidrug Resistance Protein 4); RET; STEAP1 (six transmembraneepithelial antigen of prostate); TENB2 (putative transmembraneproteoglycan); E16 (LAT1, SLC7A5); 0772P (CA125, MUC16); MPF (MPF, MSLN,SMR, megakaryocyte potentiating factor, mesothelin); Napi2b (NAPI-2B,NPTIIb, SLC34A2, solute carrier family 34 (sodium phosphate), member 2,type II sodium-dependent phosphate transporter 3b); Sema 5b; PSCA hIg(2700050C12Rik, C530008016Rik, RIKEN cDNA 2700050C12, RIKEN cDNA2700050C12 gene); ETBR (Endothelin type B receptor); MSG783 (RNF124,hypothetical protein FLJ20315); STEAP2; TrpM4 (BR22450, FLJ20041, TRPM4,TRPM4B, transient receptor potential cation channel, subfamily M, member4); CRIPTO (CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growthfactor); CD21 (CR2 (Complement receptor 2) or C3DR (C3d/Epstein Barrvirus receptor) or Hs.73792); FcRH2 (IFGP4, IRTA4, SPAP1A (SH2 domaincontaining phosphatase anchor protein 1a), SPAP1B, SPAP1C); NCA; MDP;IL20Rα; Brevican; EphB2R; ASLG659; PSCA; GEDA; BAFF-R (B cell-activatingfactor receptor, BLyS receptor 3, BR3); CXCR5 (Burkitt's lymphomareceptor 1; HLA-DOB (Beta subunit of MHC class II molecule); P2X5(Purinergic receptor P2X ligand-gated ion channel 5; CD72 (B-celldifferentiation antigen CD72, Lyb-2); LY64 (Lymphocyte antigen 64(RP105), type I membrane protein of the leucine rich repeat (LRR)family); FcRH1 (Fc receptor-like protein 1); IRTA2 (Immunoglobulinsuperfamily receptor translocation associated 2); TMEFF1; TMEM46 (shisahomolog 2 (Xenopus laevis); SHISA2); LGR5 (leucine-richrepeat-containing G protein-coupled receptor 5; GPR49, GPR67); LY6K(lymphocyte antigen 6 complex, locus K; LY6K; HSJ001348; FLJ35226);GPR19 (G protein-coupled receptor 19; Mm 4787); GPR54 (KISS1 receptor;KISS1R; GPR54; HOT7T175; AXOR12); ASPHD1 (aspartate beta-hydroxylasedomain containing 1; LOC253982); Tyrosinase (TYR; OCAIA; OCA1A;tyrosinase; SHEP3); TMEM118 (ring finger protein, transmembrane 2;RNFT2; FLJ14627); GPR172A (G protein-coupled receptor 172A; GPCR41;FLJ11856; D15Ertd747e); GPC3 (Glypican 3); CLL1 (C-Type Lectin-likemolecule 1); B7-H4 (B7x; B7S1); RNF43 (Ring finger protein 43); CD70;CXORF61 (Chromosome X open reading frame 61); HAVCR1; Epiregulin;Amphiregulin; EGFR; EGFR-L858R; EGFR-L861Q; EGFR-G719A; EGFR-G719S;EGFR-G719C; EGFR-T790M; EGFR-S7681; adipophilin; AIM-2; ALDH1A1;alpha-actinin-4; alpha-foetoprotein; ARTC1; B-RAF; BAGE-1; BCLX (L);BCR-ABL fusion protein (b3a2); beta-catenin; BING-4; CALCA; CASP-5;CASP-8; CD45; Cdc27; CDK4; CDKN2A; CEA; CLPP; COA-1; CPSF; Cw6; cyclinD1; Cyclin-A1; dek-can fusion protein; DKK1; DR1; DR13; EFTUD2;Elongation factor 2; ENAH (hMena); EpCAM; EphA3; ETV6-AML1 fusionprotein; EZH2; FLT3-ITD; FN1; G250; MN; CAIX; GAGE-1;2;8;GAGE-3;4;5;6;7; glypican-3; GnTVf; gp100/Pmel17; GPNMB; HERV-K-MEL;hsp70-2; IDO1; IGF2B3; IL13Ralpha2; Intestinal carboxyl esterase; K-ras;Kallikrein 4; KIF20A; KK-LC-1; KM-HN-1; LAGE-1;LDLR-fucosyltransferaseASfusion protein; Lengsin; M-CSF; MAGE-A1;MAGE-A10; MAGE-A12; MAGE-A2; MAGE-A3; MAGE-A4; MAGE-A6; MAGE-A9;MAGE-C1; MAGE-C2; mammaglobin-A; MART2; MCSP; mdm-2; ME1;Melan-A/MART-1; Meloe; MMP-2; MMP-7; MUC1; MUC5AC; mucin; MUM-1f; MUM-2;MUM-3; Myosin class I; N-ras; NA88-A; neo-PAP; NFYC; NY-BR-1;NY-ESO-1/LAGE-2; OA1; OGT; OS-9; p53; PAP; PAX5; PBF; pml-RARalphafusion protein; PRAME; PRDX5; PSMA; PTPRK; RAB38/NY-MEL-1; RAGE-1;RBAF600; RGS5; RhoC; RNF43; RU2AS; SAGE; secernin 1; SIRT2; SNRPD1;SOX10; Sp17; SSX-2; SSX-4; STEAP1; survivin; SYT-SSX1 or -SSX2 fusionprotein; TAG-1; TAG-2; Telomerase; TGF-betaRII; TRAG-3; Triosephosphateisomerase; TRP-1/gp75; TRP-2; TRP2-INT2; tyrosinase; VEGF; WT1;XAGE-1b/GAGED2a; and SLC35D3. In some embodiments, the tumor antigen isselected from the group consisting of CD20, FcRH5, HER2, LYPD1, LY6G6D,PMEL17, LY6E, CD19, CD33, CD22, CD79A, CD79B, EDAR, GFRA1, MRP4, RET,Steap1, and TenB2.

In some embodiments, the tumor antigen is CD20 and the second bindingdomain comprises the following six HVRs: (a) an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) an HVR-H2 comprising theamino acid sequence of SEQ ID NO: 158; (c) an HVR-H3 comprising theamino acid sequence of SEQ ID NO: 159; (d) an HVR-L1 comprising theamino acid sequence of SEQ ID NO: 160; (e) an HVR-L2 comprising theamino acid sequence of SEQ ID NO: 161; and (f) an HVR-L3 comprising theamino acid sequence of SEQ ID NO: 162.

In some embodiments, the bispecific antibody that binds to CD20 and CD3comprises an anti-CD20 arm comprising a first binding domain comprisingthe following six hypervariable regions (HVRs): an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; an HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; an HVR-H3 comprising the amino acidsequence of SEQ ID NO:159; an HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 160; an HVR-L2 comprising the amino acid sequence of SEQID NO: 161; and an HVR-L3 comprising the amino acid sequence of SEQ IDNO: 162; and an anti-CD3 arm comprising a second binding domaincomprising the amino acid sequences of any one of the following sixHVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3, respectively: SEQ IDNOs: 1-6; SEQ ID NOs: 7, 8, 181, 10, 11, and 182; SEQ ID NOs: 23, 183,25, 26, 27, and 28; SEQ ID NOs: 31-36; SEQ ID NOs: 37-42; SEQ ID NOs:43-48; SEQ ID NOs: 49-54; SEQ ID NOs: 55-60; SEQ ID NOs: 61-66; SEQ IDNOs: 67-72; SEQ ID NOs: 73-78; SEQ ID NOs: 79-84; SEQ ID NOs: 85-90; SEQID NOs: 91-96; SEQ ID NOs: 97-102; SEQ ID NOs: 103-108; SEQ ID NOs:109-114; SEQ ID NOs: 115-120; SEQ ID NOs: 121-126; SEQ ID NOs: 127-132;SEQ ID NOs: 133-138; SEQ ID NOs: 139-144; SEQ ID NOs: 145-150; SEQ IDNOs: 151-156; or SEQ ID NOs 631-636. For clarity, in these embodiments,by the six HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3,respectively: SEQ ID NOs: 1-6, is meant HVR-H1 is SEQ ID NO: 1, HVR-H2is SEQ ID NO: 2, HVR-H3 is SEQ ID NO: 3, HVR-L1 is SEQ ID NO: 4, HVR-L2is SEQ ID NO: 5, and HVR-L3 is SEQ ID NO:6. This same notation hold truefor the other similar embodiments herein, including the bispecificantibodies that bind to HER2 and CD3, FcRH5 and CD3, and LYPD1 and CD3.

In some embodiments, the second binding domain comprises (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 266; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 267; or (c) a VH domain as in (a) anda VL domain as in (b). In some embodiments, the VH domain comprises theamino acid sequence of SEQ ID NO: 266. In some embodiments, the VLdomain comprises the amino acid sequence of SEQ ID NO: 267.

In some embodiments, the tumor antigen is FcRH5 and the second bindingdomain comprises the following six HVRs: (a) an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 163; (b) an HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) an HVR-H3 comprising theamino acid sequence of SEQ ID NO: 165; (d) an HVR-L1 comprising theamino acid sequence of SEQ ID NO: 166; (e) an HVR-L2 comprising theamino acid sequence of SEQ ID NO: 167; and (f) an HVR-L3 comprising theamino acid sequence of SEQ ID NO: 168. In some embodiments, the secondbinding domain comprises (a) a VH domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 269; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 268. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 269.

In some embodiments, the tumor antigen is HER2 and the second bindingdomain comprises the following six HVRs: (a) an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) an HVR-H2 comprising theamino acid sequence of SEQ ID NO: 170; (c) an HVR-H3 comprising theamino acid sequence of SEQ ID NO: 171; (d) an HVR-L1 comprising theamino acid sequence of SEQ ID NO: 172; (e) an HVR-L2 comprising theamino acid sequence of SEQ ID NO: 173; and (f) an HVR-L3 comprising theamino acid sequence of SEQ ID NO: 174. In some embodiments, the secondbinding domain comprises (a) a VH domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 270. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 271.

In some embodiments, the tumor antigen is HER2 and the second bindingdomain comprises the following six HVRs: (a) an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) an HVR-H2 comprising theamino acid sequence of SEQ ID NO: 582; (c) an HVR-H3 comprising theamino acid sequence of SEQ ID NO: 583; (d) an HVR-L1 comprising theamino acid sequence of SEQ ID NO: 584; (e) an HVR-L2 comprising theamino acid sequence of SEQ ID NO: 585; and (f) an HVR-L3 comprising theamino acid sequence of SEQ ID NO: 586. In some embodiments, the secondbinding domain comprises (a) a VH domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 594; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 593. In some embodiments the VL domain comprisesthe amino acid sequence of SEQ ID NO: 594.

In some embodiments, the tumor antigen is HER2 and the second bindingdomain comprises the following six HVRs: (a) an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) an HVR-H2 comprising theamino acid sequence of SEQ ID NO: 588; (c) an HVR-H3 comprising theamino acid sequence of SEQ ID NO: 589; (d) an HVR-L1 comprising theamino acid sequence of SEQ ID NO: 590; (e) an HVR-L2 comprising theamino acid sequence of SEQ ID NO: 591; and (f) an HVR-L3 comprising theamino acid sequence of SEQ ID NO: 592. In some embodiments, the secondbinding domain comprises (a) a VH domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 596; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 595. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 596.

In some embodiments, the tumor antigen is RET and the second bindingdomain comprises the following six HVRs: (a) an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) an HVR-H2 comprising theamino acid sequence of SEQ ID NO: 614; (c) an HVR-H3 comprising theamino acid sequence of SEQ ID NO: 615; (d) an HVR-L1 comprising theamino acid sequence of SEQ ID NO: 616; (e) an HVR-L2 comprising theamino acid sequence of SEQ ID NO: 617; and (f) an HVR-L3 comprising theamino acid sequence of SEQ ID NO: 618. In some embodiments, the secondbinding domain comprises (a) a VH domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 619; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 620; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 619. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 620.

In some embodiments, the tumor antigen is LYPD1 and the second bindingdomain comprises the following six HVRs: (a) an HVR-H1 comprising theamino acid sequence of SEQ ID NO: 175; (b) an HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) an HVR-H3 comprising theamino acid sequence of SEQ ID NO: 177; (d) an HVR-L1 comprising theamino acid sequence of SEQ ID NO: 178; (e) an HVR-L2 comprising theamino acid sequence of SEQ ID NO: 179; and (f) an HVR-L3 comprising theamino acid sequence of SEQ ID NO: 180. In some embodiments, the secondbinding domain comprises (a) a VH domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 272; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 273; or (c) a VH domain as in (a) and a VL domainas in (b). In some embodiments, the VH domain comprises the amino acidsequence of SEQ ID NO: 272. In some embodiments, the VL domain comprisesthe amino acid sequence of SEQ ID NO: 273.

In some aspects, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises a second binding domain comprising: (a)a VH domain comprising an amino acid sequence of SEQ ID NO: 266 and (b)a VL domain comprising an amino acid sequence of SEQ ID NO: 267; (a) aVH domain comprising an amino acid sequence of SEQ ID NO: 268 and (b) aVL domain comprising an amino acid sequence of SEQ ID NO: 269; (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 270 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 271; (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 272 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 273; (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 593 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 594; (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 595 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 596; or (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 619 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 620.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises an anti-CD3 arm comprising a firstbinding domain comprising the following six HVRs: (a) an HVR-H1comprising the amino acid sequence of SEQ ID NO: 1; (b) an HVR-H2comprising the amino acid sequence of SEQ ID NO: 2; (c) an HVR-H3comprising the amino acid sequence of SEQ ID NO: 3; (d) an HVR-L1comprising the amino acid sequence of SEQ ID NO: 4; (e) an HVR-L2comprising the amino acid sequence of SEQ ID NO: 5; and (f) an HVR-L3comprising the amino acid sequence of SEQ ID NO: 6; and an anti-CD20 armcomprising a second binding domain comprising the following six HVRs:(a) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 157; (b)an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 158; (c) anHVR-H3 comprising the amino acid sequence of SEQ ID NO: 159; (d) anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e) anHVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 162.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises an anti-CD3 arm comprising a firstbinding domain comprising (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 184 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 185, and an anti-CD20 arm comprising a secondbinding domain comprising (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 266 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 267.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises an anti-CD3 arm comprising a firstbinding domain comprising (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 184 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 185, and an anti-CD20 arm comprising a secondbinding domain comprising (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 266 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 267, wherein the anti-CD3 antibody comprises anN297G substitution mutation.

In another aspect, the invention features an anti-CD3 antibody, whereinthe anti-CD3 antibody comprises an anti-CD3 arm comprising a firstbinding domain comprising (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 184 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 185, and an anti-CD20 arm comprising a secondbinding domain comprising (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 266 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 267, wherein (a) the anti-CD3 arm comprisesT366S, L368A, Y407V, and N297G substitution mutations and (b) theanti-CD20 arm comprises T366W and N297G substitution mutations.

In some embodiments, any one of the preceding anti-CD3 antibodies cancomprise one or more heavy chain constant domains, wherein the one ormore heavy chain constant domains are selected from a first CH1 (CH1₁)domain, a first CH2 (CH2₁) domain, a first CH3 (CH3₁) domain, a secondCH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂)domain. In some embodiments, at least one of the one or more heavy chainconstant domains is paired with another heavy chain constant domain. Insome embodiments, the CH3₁ and CH3₂ domains each comprise a protuberanceor cavity, and wherein the protuberance or cavity in the CH3₁ domain ispositionable in the cavity or protuberance, respectively, in the CH3₂domain. In some embodiments, the CH3₁ and CH3₂ domains meet at aninterface between said protuberance and cavity. In some embodiments, theCH2₁ and CH2₂ domains each comprise a protuberance or cavity, andwherein the protuberance or cavity in the CH2₁ domain is positionable inthe cavity or protuberance, respectively, in the CH2₂ domain. In someembodiments, the CH2₁ and CH2₂ domains meet at an interface between saidprotuberance and cavity.

In some embodiments, the half-life of any one of the preceding anti-CD3antibodies may be about 7 days.

In some embodiments, the invention features an immunoconjugatecomprising any one of the preceding anti-CD3 antibodies conjugated to acytotoxic agent. Also provided is a composition comprising any one ofthe preceding anti-CD3 antibodies. In some embodiments, the compositionfurther comprises a pharmaceutically acceptable carrier, excipient, ordiluent. In some embodiments, the composition is a pharmaceuticalcomposition. In some embodiments, the composition further comprises aPD-1 axis binding antagonist or an additional therapeutic agent. Inanother aspect, the invention features an isolated nucleic acid thatencodes any of the anti-CD3 antibodies disclosed herein, comprising avector (e.g., an expression vector) for expressing the antibody.

In another aspect, the invention features host cells comprising thepreceding nucleic acids and/or vectors. In some embodiments, the hostcell is a mammalian cell (e.g., a Chinese hamster ovary (CHO) cell). Inother embodiments, the host cell is a prokaryotic cell (e.g., an E. colicell). A method of producing any one of the preceding anti-CD3antibodies is also provided, the method comprising culturing the hostcell that produces the anti-CD3 antibody and recovering the anti-CD3antibody from the host cell or the culture medium.

In some aspects, any one of the preceding anti-CD3 antibodies can be foruse as a medicament. In some embodiments, any one of the precedinganti-CD3 antibodies can be for use in treating or delaying progressionof a cell proliferative disorder or an autoimmune disorder in a subjectin need thereof. In some embodiments, any one of the preceding anti-CD3antibodies can be for use in enhancing immune function in a subjecthaving a cell proliferative disorder or an autoimmune disorder.

In some aspects, the invention features the use of any one of thepreceding anti-CD3 antibodies in the manufacture of a medicament fortreating or delaying progression of a cell proliferative disorder or anautoimmune disorder. In some aspects, the invention features the use ofany one of the preceding anti-CD3 antibodies in the manufacture of amedicament for enhancing immune function in a subject having a cellproliferative disorder or an autoimmune disorder.

A further aspect of the invention is a method of treating or delayingthe progression of a cell proliferative disorder or an autoimmunedisorder in a subject in need thereof, the method comprisingadministering to the subject an effective amount any one of thepreceding anti-CD3 antibodies. In another aspect, the invention featuresa method of enhancing immune function in a subject having a cellproliferative disorder or an autoimmune disorder, the method comprisingadministering to the subject any one of the preceding anti-CD3antibodies. In some embodiments, the anti-CD3 antibody binds to (a) aCD3 molecule located on an immune effector cell and (b) a secondbiological molecule located on a target cell other than the immuneeffector cell. In some embodiments, the anti-CD3 antibody activates theimmune effector cell following binding to (a) and (b). In someembodiments, the activated immune effector cell is capable of exerting acytotoxic effect and/or an apoptotic effect on the target cell. In someembodiments, the anti-CD3 antibody is administered to the subject in adosage of about 0.01 mg/kg to about 10 mg/kg. In some embodiments, theanti-CD3 antibody is administered to the subject in a dosage of about0.1 mg/kg to about 10 mg/kg. In some embodiments, the anti-CD3 antibodyis administered to the subject in a dosage of about 1 mg/kg. In someembodiments, the anti-CD3 antibody is administered subcutaneously,intravenously, intramuscularly, topically, orally, transdermally,intraperitoneally, intraorbitally, by implantation, by inhalation,intrathecally, intraventricularly, or intranasally. In some embodiments,the anti-CD3 antibody is administered subcutaneously. In someembodiments, the anti-CD3 antibody is administered intravenously.

In some embodiments, the method further comprises administering to thesubject a PD-1 axis binding antagonist or an additional therapeuticagent. In some embodiments, the additional therapeutic agent isadministered prior to or subsequent to the administration of theanti-CD3 antibody. In some embodiments, the additional therapeutic agentis administered concurrently with the anti-CD3 antibody. In someembodiments, the PD-1 axis binding antagonist is selected from the groupconsisting of a PD-1 binding antagonist, a PD-L1 binding antagonist, anda PD-L2 binding antagonist. In some embodiments, the PD-1 axis bindingantagonist is a PD-1 binding antagonist. In some embodiments, the PD-1binding antagonist is selected from the group consisting of MDX-1106(nivolumab), MK-3475 (lambrolizumab), CT-011 (pidilizumab), and AMP-224.In other embodiments, the PD-1 axis binding antagonist is a PD-L1binding antagonist. In some embodiments, the PD-L1 binding antagonist isselected from the group consisting of: YW243.55.S70, MPDL3280A,MDX-1105, and MED14736. In other embodiments, the PD-1 axis bindingantagonist is a PD-L2 binding antagonist. In some embodiments, the PD-L2binding antagonist is an antibody or an immunoadhesin.

In some aspects, the invention features a method of treating or delayingthe progression of a cell proliferative disorder or an autoimmunedisorder in a subject in need thereof, the method comprisingadministering to the subject an anti-CD3 antibody and a PD-1 axisbinding antagonist, wherein the anti-CD3 antibody comprises an anti-CD3arm and an anti-CD20 arm. In some aspects, the invention features amethod of enhancing immune function in a subject having a cellproliferative disorder or an autoimmune disorder, the method comprisingadministering to the subject an anti-CD3 antibody and a PD-1 axisbinding antagonist, wherein the anti-CD3 antibody comprises an anti-CD3arm and an anti-CD20 arm (i.e., a CD20 TDB). In some embodiments, (a)the anti-CD3 arm comprises a first binding domain comprising (i) a VHdomain comprising an amino acid sequence of SEQ ID NO: 184, and (ii) aVL domain comprising an amino acid sequence of SEQ ID NO: 185; (b) theanti-CD20 arm comprises a second binding domain comprising (i) a VHdomain comprising an amino acid sequence of SEQ ID NO: 266, and (ii) aVL domain comprising an amino acid sequence of SEQ ID NO: 267; and/or(c) the PD-1 axis binding antagonist is an anti-PD-L1 antibody.

In some embodiments, the anti-CD3 antibody comprises an anti-CD20 armcomprising a N297G substitution mutation. In some embodiments, theanti-CD3 antibody comprises an anti-CD3 arm comprising T366S, L368A,Y407V, and/or N297G substitution mutation(s) and an anti-CD20 armcomprising T366W and/or N297G substitution mutation(s). In someembodiments, the anti-CD3 antibody comprises an anti-CD3 arm comprisinga N297G substitution mutation. In some embodiments, the anti-CD3antibody comprises an anti-CD20 arm comprising T366S, L368A, Y407V,and/or N297G substitution mutation(s) and an anti-CD3 arm comprisingT366W and/or N297G substitution mutation(s).

In some embodiments, the anti-CD3 antibody comprises an anti-HER2 armcomprising a N297G substitution mutation. In some embodiments, theanti-CD3 antibody comprises an anti-CD3 arm comprising T366S, L368A,Y407V, and/or N297G substitution mutation(s) and an anti-HER2 armcomprising N297G, N297A, L234A, L235A, and/or D265A substitutionmutation(s). In some embodiments, the anti-CD3 antibody comprises ananti-CD3 arm comprising a N297G substitution mutation. In someembodiments, the anti-CD3 antibody comprises an anti-HER2 arm comprisingT366S, L368A, Y407V, and/or N297G substitution mutation(s) and ananti-CD3 arm comprising N297G, N297A, L234A, L235A, and/or D265Asubstitution mutation(s).

In some embodiments, the method further comprises administering to thesubject a glucocorticoid. In some embodiments, the glucocorticoid isselected from the group consisting of dexamethasone, hydrocortisone,cortisone, prednisolone, prednisone, methylprednisone, triamcinolone,paramethasone, betamethasone, fludrocortisone, and pharmaceuticallyacceptable esters, salts, and complexes thereof. In some embodiments,the glucocorticoid is dexamethasone. In some embodiments, theglucocorticoid is a pharmaceutically acceptable ester, salt, or complexof dexamethasone.

In some embodiments, the method further comprises administering to thesubject rituximab.

In some embodiments, the method further comprises administering to thesubject obinutuzumab.

In some embodiments, the method further comprises administering to thesubject an antibody-drug conjugate (ADC).

In any of the preceding uses or methods, the cell proliferative disordercan be cancer. In some embodiments, the cancer is selected from thegroup consisting of breast cancer, colorectal cancer, non-small celllung cancer, non-Hodgkin's lymphoma (NHL), B cell lymphoma, B cellleukemia, multiple myeloma, renal cancer, prostate cancer, liver cancer,head and neck cancer, melanoma, ovarian cancer, mesothelioma,glioblastoma, germinal-center B-cell-like (GCB) DLBCL, activatedB-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma(MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL),marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL),lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM),central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cellprolymphocytic leukemia, Splenic marginal zone lymphoma, Hairy cellleukemia, Splenic lymphoma/leukemia, unclassifiable, Splenic diffuse redpulp small B-cell lymphoma, Hairy cell leukemia variant, Waldenströmmacroglobulinemia, Heavy chain diseases, a Heavy chain disease, γ Heavychain disease, μ Heavy chain disease, Plasma cell myeloma, Solitaryplasmacytoma of bone, Extraosseous plasmacytoma, Extranodal marginalzone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma),Nodal marginal zone lymphoma, Pediatric nodal marginal zone lymphoma,Pediatric follicular lymphoma, Primary cutaneous follicle centrelymphoma, T-cell/histiocyte rich large B-cell lymphoma, Primary DLBCL ofthe CNS, Primary cutaneous DLBCL, leg type, EBV-positive DLBCL of theelderly, DLBCL associated with chronic inflammation, Lymphomatoidgranulomatosis, Primary mediastinal (thymic) large B-cell lymphoma,Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma,Plasmablastic lymphoma, Large B-cell lymphoma arising in HHV8-associatedmulticentric Castleman disease, Primary effusion lymphoma: B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and Burkitt lymphoma, and B-cell lymphoma,unclassifiable, with features intermediate between diffuse large B-celllymphoma and classical Hodgkin lymphoma. In some embodiments, thepreferred cancer is germinal-center B-cell-like (GCB) DLBCL, activatedB-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma(MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL),marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL),lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM),central nervous system lymphoma (CNSL), or Burkitt's lymphoma (BL)

In any of the preceding uses or methods, the autoimmune disorder can beselected from the group consisting of rheumatoid arthritis, juvenilerheumatoid arthritis, systemic lupus erythematosus (SLE), Wegener'sdisease, inflammatory bowel disease, idiopathic thrombocytopenic purpura(ITP), thrombotic thrombocytopenic purpura (TTP), autoimmunethrombocytopenia, multiple sclerosis, psoriasis, IgA nephropathy, IgMpolyneuropathies, myasthenia gravis, vasculitis, diabetes mellitus,Reynaud's syndrome, Sjorgen's syndrome, glomerulonephritis,Neuromyelitis Optica (NMO) and IgG neuropathy.

In another aspect, the invention features a kit comprising: (a) acomposition comprising any one of the preceding anti-CD3 antibodies and(b) a package insert comprising instructions for administering thecomposition to a subject to treat or delay progression of a cellproliferative disorder.

In any of the preceding uses or methods, the subject can be a human.

BRIEF DESCRIPTION OF THE DRAWINGS

The application file contains at least one drawing executed in color.Copies of this patent or patent application with color drawings will beprovided by the Office upon request and payment of the necessary fee.

FIG. 1 shows the amino acid sequence of single-chain human CD3εγ with a26-mer linker sequence used in CD3 epitope mapping experiments (SEQ IDNO: 282).

FIG. 2A is a table summarizing the characterization of select hybridomaclones. The table summarizes the results of ELISA CD3 bindingexperiments using human and cyno CD3ε¹⁻²⁷-Fc; FACS binding experimentsusing human Jurkat T cells, human PBMCs, and cyno PBMCs; T cellactivation experiments using FACS analysis; and isotype determinationexperiments.

FIG. 2B is a table summarizing the binding affinities (Kd values) ofselect hybridoma clones for a commercial human CD3εγ antigen.

FIG. 3A is a table summarizing the characterization of select hybridoma.The table summarizes the results of ELISA CD3 binding experiments usinghuman and cyno CD3ε¹⁻²⁷-Fc; FACS binding experiments using human JurkatT cells, human PBMCs, and cyno PBMCs; T cell activation experimentsusing FACS analysis; and isotype determination experiments.

FIGS. 3B and 3C are tables summarizing the binding affinities (Kdvalues) of select hybridoma clones.

FIG. 4A shows the amino acid sequences of the light chain variabledomains of the anti-CD3 antibodies. HVR sequences are delimited by thedenoted boxes for each of the antibodies.

FIG. 4B shows the amino acid sequences of the light chain variabledomains of the anti-CD3 antibodies.

FIG. 4C shows the amino acid sequences of the heavy chain variabledomains of the anti-CD3 antibodies.

FIG. 5A shows the amino acid sequences of the light chain variabledomains of the anti-CD3 antibodies.

FIG. 5B shows the amino acid sequences of the heavy chain variabledomains of the anti-CD3 antibodies.

FIG. 6A shows the amino acid sequences of the light chain variabledomains of anti-CD3 antibody 21A9, and Rab17.

FIG. 6B shows the amino acid sequences of the heavy chain variabledomain of anti-CD3 antibody 21A9, and Rab17.

FIG. 7 is a sequence alignment of light chain variable domain (top) andheavy chain variable domain (bottom) amino acid sequences of anti-CD3antibodies showing the consensus sequence, 40G5c, derived from therelated clonal antibodies.

FIG. 8A is a sequence alignment of light chain variable domain (top) andheavy chain variable domain (bottom) amino acid sequences of anti-CD3antibody 13A3 and a humanized variant thereof (hu13A3).

FIG. 8B is a sequence alignment of light chain variable domain (top) andheavy chain variable domain (bottom) amino acid sequences of anti-CD3antibody 30A1 and a humanized variant thereof (hu30A1).

FIG. 8C is a sequence alignment of light chain variable domain (top) andheavy chain variable domain (bottom) amino acid sequences of anti-CD3antibody 41 D9a and a humanized variant thereof (hu41 D9a).

FIG. 8D is a sequence alignment of light chain variable domain (top) andheavy chain variable domain (bottom) amino acid sequences of anti-CD3antibody SP34 and a humanized variant thereof (huSP34).

FIG. 8E is a sequence alignment of light chain variable domain (top) andheavy chain variable domain (bottom) amino acid sequences of anti-CD3antibody 38E4 and a humanized variant thereof (hu38E4).

FIG. 8F is a sequence alignment of light chain variable domain (top) andheavy chain variable domain (bottom) amino acid sequences of anti-CD3antibody 40G5 and a humanized variant thereof (hu40G5).

FIG. 9A is a table summarizing selected humanized variants of anti-CD3antibody 13A3 and their binding affinities, assayed using commercialCD3ε (Creative Biomart, Shirley, N.Y.; Catalog Number CD3E-2194H).

FIG. 9B is a table summarizing selected humanized variants of anti-CD3antibody 30A1 and their binding affinities, assayed using commercialCD3ε (Creative Biomart, Shirley, N.Y.; Catalog Number CD3E-2194H).

FIG. 9C is a table summarizing selected humanized variants of anti-CD3antibody 41 D9a and their binding affinities, assayed using commercialCD3ε (Creative Biomart, Shirley, N.Y.; Catalog Number CD3E-2194H).

FIG. 9D is a table summarizing selected humanized variants of anti-CD3antibody SP34 and their binding affinities, assayed using commercialCD3ε (Creative Biomart, Shirley, N.Y.; Catalog Number CD3E-2194H).

FIG. 9E is a table summarizing selected humanized variants of anti-CD3antibody 38E4 and their binding affinities, assayed using commercialCD3ε (Creative Biomart, Shirley, N.Y.; Catalog Number CD3E-2194H).

FIG. 9F is a table summarizing selected humanized variants of anti-CD3antibody 40G5c and their binding affinities, assayed using commercialCD3ε (Creative Biomart, Shirley, N.Y.; Catalog Number CD3E-2194H).

FIG. 10 is a table summarizing the binding affinity of humanizedanti-CD3 antibodies for various CD3ε antigens.

FIG. 11 is a table summarizing the binding affinity of humanizedanti-CD3 antibodies 38E4v1 through 38E4v9 and 40G5c, as measured byBiacore with human CD3εγ on chip and anti-CD3 antibodies in flowthrough.

FIG. 12A is a table summarizing the relative binding affinities forsingle alanine, serine, threonine, or glutamate mutants of the humanizedanti-CD3 antibody 38E4v1 having a single mutation in either HVR-L3 orHVR-H3, as compared to 38E4v1 using single-cycle or conventionalmulti-cycle kinetic Biacore analysis.

FIG. 12B shows the HVR-L3 (top) and HVR-H3 (bottom) amino acid sequencesof the humanized anti-CD3 antibody 38E4v1.

FIG. 13A is a series of graphs showing the relative binding of thedenoted anti-CD3 antibody to alanine variants of CD3ε¹⁻²⁷-Fc.

FIG. 13B is a graph showing the relative fraction of CD3εγ alaninescanning phagemid mutants bound to anti-CD3 antibodies 38E4.v1, 40G5c,and SP34.v52, as compared to wild-type CD3εγ phage binding.

FIG. 13C is a series of graphs showing the relative binding of anti-CD3antibodies 38E4.v1, 40G5c, and SP34.v52 to selected CD3εγ alaninescanning phagemid mutants as a function of phage concentration.

FIG. 13D is a set of tables showing the relative binding affinities ofanti-CD3 antibodies SP34.v52 and 38E4v1 to selected CD3εγ alaninescanning mutants, as assessed by Biacore. NB=no detectable binding.

FIG. 14A shows the sequence of the 16-mer CD3ε polypeptide used inco-crystallization trials with 38E4.v1 Fab.

FIGS. 14B-14F is a series of renderings of the crystal structure showingdifferent views of the hu38E4.v1 Fab/CD3ε peptide complex.

FIG. 14G is a sequence alignment of light chain variable domain (top)and heavy chain variable domain (bottom) amino acid sequences ofanti-CD3 antibodies hu40G5c and hu38E4.v1, with residues of eachantibody that are important for binding CD3 (contact residues) circledin the alignment. The circled residues were found to be within 5 Å ofthe CD3 peptide, as determined by crystallographic analysis. Δ denotesvernier positions (for reference, see, e.g., Foote and Winter. JMB. 224:487, 1992); * denotes FW-HVR interactions (for reference, see, e.g.,Padlan et al. Mol. Immunol. 31: 169, 1994); and ● denotes VH-VLinteractions (for reference, see, e.g., Padlan et al. Mol. Immunol. 31:169, 1994).

FIG. 14H is a rendering of the crystal structure of CD3ε polypeptidebound by hu38E4.v1 Fab. All antigen contact residues are depicted inyellow. All contact residues are identical between hu38E4.v1 and hu40G5,except G96 (depicted in orange) is S96 in hu40G5.

FIGS. 14I and 14J are ribbon diagram renderings of the crystalstructures of hu38E4.v1 Fab and SP34v52 Fab, respectively, in the sameorientation, overlaid with VL region with a RMS=2.24.

FIG. 14K is a space-filling model rendering of the hu38E4.v1 Fabcomplexed with the CD3ε N-terminal peptide bound in the cleft betweenthe heavy (cyan) and light (purple) chains.

FIG. 14L is a space-filling model rendering of the SP34v52 Fab with theCD3ε N-terminal peptide superimposed in the same orientation as in theCD3ε/hu38E4.v1 Fab complex depicted in FIG. 14K. Residues R50 and R52(in orange) of HVR-H2 of the SP34v52 Fab are important for binding CD3.Clear clashes of the CD3 peptide with SP34v52 Fab are indicated byarrows.

FIG. 14M is a crystal structure rendering of the hu38E4.v1 complexedwith the N-terminal peptide of CD3εγ and illustrates the keyintermolecular interactions involved in the first pyroglutamine residueand the sixth residue (E6) in CD3εγ. The potential hydrogen bonds areshown as dashed lines.

FIG. 14N is a space-filling model rendering of the hu38E4.v1 Fabcomplexed with the CD3εγ N-terminal peptide bound in the cleft betweenthe heavy (cyan) and light (purple) chains. The fifth residue (E5) asillustrated, points away from the interactive site that contains thesixth residue (E6) of CD3εγ N-terminal peptide and Fab complex.

FIG. 15 depicts a schematic generalization of TDB antibody formation.The particular TDB depicted is shown as a full-length TDB inknob-in-hole (KIH) format, which can possess an aglycosylation mutation,if produced by a eukaryotic cell (e.g., a CHO cell). In an alternativeformat, the knob may be present on the anti-CD3 arm, and the hole may bepresent on the anti-tumor antigen arm. This format may also possess anaglycosylation mutation, if produced by a eukaryotic cell (e.g., a CHOcell).

FIG. 16 are graphs showing the results of FACS in vitro binding assaysof various CD3/CD20 TDBs having different combinations of UCHT1 seriesanti-CD3 arms and 2H7 series anti-CD20 arms. Bjab B tumor cell linebinding (CD20 binding), left. Jurkat cell binding (CD3 binding), right.

FIG. 17 is a set of tables summarizing the monovalent (top) and(bivalent) binding affinities as Kd values for various CD3/CD20 TDBshaving different combinations of UCHT1 series anti-CD3 arms and 2H7series anti-CD20 arms.

FIG. 18 is a graph showing the results of in vitro Jurkat cell binding(CD3 binding) FACS assays of various CD3/CD20 TDBs having differentcombinations of anti-CD3 arms with the anti-CD20 arm of 2H7v16.

FIG. 19 is a graph showing the results of in vitro Jurkat cell binding(CD3 binding) FACS assays of various CD3/CD20 TDBs having differentcombinations of anti-CD3 arms with the anti-CD20 arm of 2H7v16.

FIG. 20 is a graph showing the results of in vitro Bjab cell binding(CD20 binding) FACS assays of various CD3/CD20 TDBs having differentcombinations of anti-CD3 arms with the anti-CD20 arm of 2H7v16.

FIGS. 21A and 21B are graphs showing the results of in vitro Jurkat cellbinding (CD3 binding) FACS assays of various CD3/CD20 TDBs havingdifferent combinations of anti-CD3 arms with the anti-CD20 arm of2H7v16.

FIG. 21C is a table summarizing the EC50 (μg/ml) for each CD3/CD20 TDBtested in FIGS. 21A and 21B.

FIGS. 22A and 22B are graphs showing the results of in vitro Bjab cellbinding (CD20 binding) FACS assays of various CD3/CD20 TDBs havingdifferent combinations of anti-CD3 arms with the anti-CD20 arm of2H7v16.

FIG. 23 is a graph showing the results of in vitro Jurkat cell binding(CD3 binding) FACS assays of various CD3/CD20 TDBs having differentcombinations of anti-CD3 arms with the anti-CD20 arm of 2H7v16.

FIG. 24 is a table summarizing the binding affinities for variousCD3/CD20 TDBs and Fabs, as measured by Biacore analysis with human CD3εγon chip and CD3/CD20 TDB or Fab in flow through.

FIG. 25A is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of specified CD3/CD20 TDB (2H7 series) with 20,000 Bjab cellsand 5× purified hu CD8+ T cells.

FIG. 25B is a graph showing the percentage of Bjab killing relative to anon-TDB treated control, after 24 hours of incubation of specifiedCD3/CD20 TDB (2H7 series) with 20,000 Bjab cells and 5× purified huCD8+T cells, as measured by FACS analysis.

FIG. 26A is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of specified CD3/CD20 TDB (2H7 series) with 200,000 humanPBMCs per well.

FIG. 26B is a graph showing the percentage of endogenous (endo) B cellkilling relative to a non-TDB treated control, after 24 hours ofincubation of specified CD3/CD20 TDB (2H7 series) with 200,000 humanPBMCs per well, as measured by FACS analysis.

FIG. 27A is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of specified CD3/CD20 TDB (UCHT1 series) with 20,000 Bjabcells and 5× purified hu CD8+ T cells.

FIG. 27B is a graph showing the percentage of Bjab killing relative to anon-TDB treated control, after 24 hours of incubation of specifiedCD3/CD20 TDB (UCHT1 series) with 20,000 Bjab cells and 5× purifiedhuCD8+ T cells, as measured by FACS analysis.

FIG. 28A is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of specified CD3/CD20 TDB (UCHT1 series) with 200,000 humanPBMCs per well.

FIG. 28B is a graph showing the percentage of endo B cell killingrelative to a non-TDB treated control, after 24 hours of incubation ofspecified CD3/CD20 TDB (UCHT1 series) with 200,000 human PBMCs per well,as measured by FACS analysis.

FIG. 29A is a graph showing the percentage of endo B cell killingrelative to a non-TDB treated control, after 24 hours of incubation ofvarious CD3/CD20 TDBs having different combinations of anti-CD3 armswith the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs (isolatedfrom Donor #3) per well, as measured by FACS analysis.

FIG. 29B is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #3) per well, as measured by FACS analysis.

FIG. 30A is a graph showing the percentage of endo B cell killingrelative to a non-TDB treated control, after 24 hours of incubation ofvarious CD3/CD20 TDBs having different combinations of anti-CD3 armswith the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs (isolatedfrom Donor #4) per well, as measured by FACS analysis.

FIG. 30B is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #4) per well, as measured by FACS analysis.

FIG. 31A is a graph showing the percentage of endo B cell killingrelative to a non-TDB treated control, after 24 hours of incubation ofvarious CD3/CD20 TDBs having different combinations of anti-CD3 armswith the anti-CD20 arm of 2H7v16, with 200,000 cyno PBMCs (isolated fromDonor #2) per well, as measured by FACS analysis.

FIG. 31B is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 cyno PBMCs(isolated from Donor #2) per well, as measured by FACS analysis.

FIG. 32A is a graph showing the percentage of endo B cell killingrelative to a non-TDB treated control, after 24 hours of incubation ofvarious CD3/CD20 TDBs having different combinations of anti-CD3 armswith the anti-CD20 arm of 2H7v16, with 200,000 cyno PBMCs (isolated fromDonor #3) per well, as measured by FACS analysis.

FIG. 32B is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 cyno PBMCs(isolated from Donor #3) per well, as measured by FACS analysis.

FIG. 33A is a graph showing the percentage of Bjab cell killing relativeto a non-TDB treated control, after 24 hours of incubation of variousCD3/CD20 TDBs having different combinations of anti-CD3 arms with theanti-CD20 arm of 2H7v16, with 200,000 cyno PBMCs per well, as measuredby FACS analysis.

FIG. 33B is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 cyno PBMCsper well, as measured by FACS analysis.

FIG. 34A is a graph showing the percentage of endo B cell killingrelative to a non-TDB treated control, after 24 hours of incubation ofvarious CD3/CD20 TDBs having different combinations of anti-CD3 armswith the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs (isolatedfrom Donor #2) per well, as measured by FACS analysis.

FIG. 34B is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #2) per well, as measured by FACS analysis.

FIG. 35A is a graph showing the percentage of endo B cell killingrelative to a non-TDB treated control, after 24 hours of incubation ofvarious CD3/CD20 TDBs having different combinations of anti-CD3 armswith the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs (isolatedfrom Donor #3) per well, as measured by FACS analysis.

FIG. 35B is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #3) per well, as measured by FACS analysis.

FIG. 36A is a graph showing the percentage of endo B cell killingrelative to a non-TDB treated control, after 24 hours of incubation ofvarious CD3/CD20 TDBs having different combinations of anti-CD3 armswith the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs (isolatedfrom Donor #4) per well, as measured by FACS analysis.

FIG. 36B is a graph showing the percentage of T cell activation, asmeasured by CD69 and CD25 surface expression, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #4) per well, as measured by FACS analysis.

FIGS. 37A and 37B are graphs showing the percentage of T cellactivation, as measured by CD69 and CD25 surface expression, after 24hours of incubation of various CD3/CD20 TDBs having differentcombinations of anti-CD3 arms with the anti-CD20 arm of 2H7v16, with200,000 human PBMCs (isolated from Donor #1) per well, as measured byFACS analysis.

FIG. 37C is a table summarizing the CD8+ T cell activation EC50 (ng/ml)for each CD3/CD20 TDB tested in FIGS. 37A and 37B.

FIGS. 38A and 38B are graphs showing the percentage of endo B cellkilling relative to a non-TDB treated control, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #1) per well, as measured by FACS analysis.

FIG. 38C is a table summarizing the endo B cell killing EC50 (ng/ml) foreach CD3/CD20 TDB tested in FIGS. 38A and 38B.

FIGS. 39A and 39B are graphs showing the percentage of T cellactivation, as measured by CD69 and CD25 surface expression, after 48hours of incubation of various CD3/CD20 TDBs having differentcombinations of anti-CD3 arms with the anti-CD20 arm of 2H7v16, with200,000 human PBMCs (isolated from Donor #1) per well, as measured byFACS analysis.

FIG. 39C is a table summarizing the CD8+ T cell activation EC50 (ng/ml)for each CD3/CD20 TDB tested in FIGS. 39A and 39B.

FIGS. 40A and 40B are graphs showing the percentage of endo B cellkilling relative to a non-TDB treated control, after 48 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #1) per well, as measured by FACS analysis.

FIG. 40C is a table summarizing the endo B cell killing EC50 (ng/ml) foreach CD3/CD20 TDB tested in FIGS. 40A and 40B.

FIGS. 41A and 41B are graphs showing the percentage of T cellactivation, as measured by CD69 and CD25 surface expression, after 24hours of incubation of various CD3/CD20 TDBs having differentcombinations of anti-CD3 arms with the anti-CD20 arm of 2H7v16, with200,000 human PBMCs (isolated from Donor #2) per well, as measured byFACS analysis.

FIG. 41C is a table summarizing the CD8+ T cell activation EC50 (ng/ml)for each CD3/CD20 TDB tested in FIGS. 41A and 41B.

FIGS. 42A and 42B are graphs showing the percentage of endo B cellkilling relative to a non-TDB treated control, after 24 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #2) per well, as measured by FACS analysis.

FIG. 42C is a table summarizing the endo B cell killing EC50 (ng/ml) foreach CD3/CD20 TDB tested in FIGS. 42A and 42B.

FIGS. 43A and 43B are graphs showing the percentage of T cellactivation, as measured by CD69 and CD25 surface expression, after 48hours of incubation of various CD3/CD20 TDBs having differentcombinations of anti-CD3 arms with the anti-CD20 arm of 2H7v16, with200,000 human PBMCs (isolated from Donor #2) per well, as measured byFACS analysis.

FIG. 43C is a table summarizing the CD8+ T cell activation EC50 (ng/ml)for each CD3/CD20 TDB tested in FIGS. 43A and 43B.

FIGS. 44A and 44B are graphs showing the percentage of endo B cellkilling relative to a non-TDB treated control, after 48 hours ofincubation of various CD3/CD20 TDBs having different combinations ofanti-CD3 arms with the anti-CD20 arm of 2H7v16, with 200,000 human PBMCs(isolated from Donor #2) per well, as measured by FACS analysis.

FIG. 44C is a table summarizing the endo B cell killing EC50 (ng/ml) foreach CD3/CD20 TDB tested in FIGS. 44A and 44B.

FIG. 45A is a graph showing that certain CD3/CD20 TDBs, such as onehaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 72H6, do notexhibit in vitro potency, as assessed by Bjab killing assays.

FIGS. 45B and 45C are graphs showing that certain CD3/CD20 TDBs, such asone having an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 72H6, donot exhibit in vitro potency, as assessed by endo B cell killing (B) andT cell activation (C) assays.

FIG. 46A is a graph showing that certain CD3/CD20 TDBs, such as onehaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 13A3, exhibitlow in vitro potency, as assessed by Bjab killing assays.

FIG. 46B is a graph showing that certain CD3/CD20 TDBs, such as onehaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 30A1, exhibitlow in vitro potency, as assessed by Bjab killing assays.

FIG. 46C is a graph showing that certain CD3/CD20 TDBs, such as onehaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 41 D9a, exhibitlow in vitro potency, as assessed by Bjab killing assays. Bjab cellkilling EC50 (ng/ml) values for each CD3/CD20 TDB tested are shown.

FIG. 46D is a graph showing that certain CD3/CD20 TDBs, such as onehaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 41 D9a, exhibitlow in vitro potency, as assessed by endo B cell killing assays. Endo Bcell killing EC50 (ng/ml) values for each CD3/CD20 TDB tested are shown.

FIG. 46E is a graph showing that certain CD3/CD20 TDBs, such as onehaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of 41 D9a, exhibitlow in vitro potency, as assessed by T cell activation assays.

FIG. 47A is a graph showing that certain CD3/CD20 TDBs, such as TDBshaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of UCHT1v9, 21A9,and 40G5c, exhibit high in vitro potency, as assessed by endo B cellkilling assays using 200,000 human PBMCs (isolated from Donor #1) perwell, as measured by FACS analysis.

FIG. 47B is a graph showing that certain CD3/CD20 TDBs, such as TDBshaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of UCHT1v9, 21A9,and 40G5c, exhibit high in vitro potency, as assessed by T cellactivation assays using 200,000 human PBMCs (isolated from Donor #1) perwell, as measured by FACS analysis.

FIG. 48A is a graph showing that certain CD3/CD20 TDBs, such as TDBshaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of UCHT1v9, 21A9,and 40G5c, exhibit high in vitro potency, as assessed by endo B cellkilling assays using 200,000 human PBMCs (isolated from Donor #2) perwell, as measured by FACS analysis.

FIG. 48B is a graph showing that certain CD3/CD20 TDBs, such as TDBshaving an anti-CD20 arm of 2H7v16 and an anti-CD3 arm of UCHT1v9, 21A9,and 40G5c, exhibit high in vitro potency, as assessed by T cellactivation assays using 200,000 human PBMCs (isolated from Donor #2) perwell, as measured by FACS analysis.

FIG. 49 is a table summarizing the in vitro potencies of variousCD3/CD20 TDBs having different combinations of anti-CD3 arms with theanti-CD20 arm of 2H7v16.

FIG. 50 shows the amino acid sequences of the light chain variabledomain (top) and heavy chain variable domain (bottom) of anti-CD20antibody 2H7.v16.

FIG. 51 shows the amino acid sequences of the light chain variabledomain (top) and heavy chain variable domain (bottom) of anti-CD3antibody hu40G5c.

FIGS. 52A and 52B show that purified CD3/CD20 TDB (40G5c/2H7v16) has nodetectable aggregate formation as determined by size-exclusionchromatography (SEC) (A) and no detectable homodimer formation (i.e.,CD3/CD3 or CD20/CD20 antibody formation) as assessed by massspectrometry (B).

FIG. 53A is a graph showing the pharmacokinetics of serum concentrationsof CD3/CD20 TDBs at varying doses in Sprague Dawley (SD) rats over time(in days), as assessed by generic immunoglobulin pharmacokinetic (GRIP)or specific assay.

FIG. 53B is a table summarizing the quantified clearance (ml/day/kg)values of the tested CD3/CD20 TDB antibodies at each dosage tested inFIG. 53A.

FIG. 54A is a graph showing that F(ab′)₂ portion of CD20 TDB retainedthe same potency as the full-length IgG CD20 TDB in B cell killing (Bjabkilling) in vitro. 20,000 Bjab cells and 200,000 PBMCs isolated fromhealthy donor were incubated with various concentration of full lengthCD20 TDB or F(ab′)2 CD20 TDB for 24 hours.

FIG. 54B is a graph showing that B cell killing activity of CD20 TDB isT cell-dependent, as no B cell killing was detected with PBMCs depletedof CD3+ T cells. 20,000 Bjab cells and 200,000 PBMCs isolated fromhealthy donor, or 200,000 PBMCs depleted of CD3+ T cells, were incubatedwith various concentration of CD20 TDB for 24 hours.

FIG. 54C is a graph showing that comparable B cell killing can beachieved with either CD4+ or CD8+ T cells as effectors. 20,000 Bjabcells and 100,000 purified CD8+ T cells or CD4+ T cells were incubatedwith various concentration of CD20 TDB for 24 hours. Cell killing and Tcell activation marked as CD69+CD25+ were measured and calculated asdescribed below.

FIG. 54D is a graph showing that CD20 TDB is capable of activating bothCD4+ and CD8+ T cells. 20,000 Bjab cells and 100,000 purified CD8+ Tcells or CD4+ T cells were incubated with various concentration of CD20TDB for 24 hours. Cell killing and T cell activation marked asCD69+CD25+ were measured and calculated as described below.

FIG. 54E is a graph showing that Granzyme upregulation is more prevalentwithin CD8+ T cells upon CD20 TDB addition. 20,000 Bjab cells and100,000 purified CD8+ T cells or CD4+ T cells were incubated withvarious concentration of CD20 TDB for 24 hours. Granzyme B induction wasalso detected by FACS.

FIG. 54F is a graph showing that a higher level of perforin release isassociated with CD8+ T cells upon CD20 TDB addition. 20,000 Bjab cellsand 100,000 purified CD8+ T cells or CD4+ T cells were incubated withvarious concentration of CD20 TDB for 24 hours. Perforin concentrationin media was measured by ELISA FIG. 55 is a series of flow cytometrygraphs showing that activated T cells are capable of proliferation inthe presence of CD20 TDB and Bjab cells.

FIG. 56A is a series of graphs showing the dose-response B cell killingcurves of 8 B leukemia/lymphoma tumor cell lines (left) and the CD20expression levels for the given B cell lines with an isotype control ingrey, as measured by FACS. B cells were cultured in RPMI 1640 mediasupplemented with 10% FBS. For the killing assay, 20,000 B cells wereincubated with 200,000 PBMCs isolated from healthy donor with variousconcentration of CD20 TDB for 24 hours.

FIG. 56B is a graph showing a wide range in the mean CD20 expression onthe 8 B cell lines tested in FIG. 56A. CD4+ T or CD8+ T cells, purifiedfrom healthy donor whole blood and CFSE-labeled, were incubated alone,with Bjab only, with CD20 TDB only, or with Bjab and CD20 TDB for 24hours first, then cells were washed and put in fresh media for another48 hours. CFSE intensity of T cells was detected by FACS, showingproliferation of T cells only in presence of Bjab and CD20 TDB.

FIG. 56C is a set of graphs showing that CD20 TDB is potent in killingall 8 lines in a dose-dependent manner, with EC50 values of B cellkilling (ng/ml) (top) and the percentage of B cell killing (bottom)represented as a function of CD20 expression on the target B cell.

FIG. 56D is a graph showing that TDBs targeting 5 different B cellantigens are comparable in mediating T cell killing of Bjab cells. Bcells were cultured in RPMI 1640 media supplemented with 10% FBS. Forthe killing assay, 20,000 Bjab cells were incubated with 100,000purified CD8+ T cells from healthy donor with a CD20 TDB (TDB A:2H7v16/UCHT1v9) or a TDB targeting a different B cell antigen (i.e.,TDBs B-E, each targeting a different B cell antigen) at a concentrationof 1000 ng/ml for 24 hours.

FIG. 56E is a graph showing the extent of B cell killing for 10 Bleukemia/lymphoma tumor cell lines. B cells were cultured in RPMI 1640media supplemented with 10% FBS. For the killing assay, 20,000 B cellswere incubated with 100,000 purified CD8+ T cells from healthy donor and1000 ng/ml CD20 TDB (2H7v16/UCHT1v9) for 24 hours.

FIG. 56F is a graph showing the dose-responsive killing curves for 8random donors.

FIG. 56G is a summary plot graph for EC50 (left) and extent of B cellkilling (right) with 1000 ng/ml antibody in a 24 hour assay for 30donors.

FIG. 56H is a set of graphs showing that the extent of B cell killingwithin 24 hours by CD20 TDB is very comparable or higher than B cellkilling by CD19 scFv. For autologous B cell killing, 200,000 PBMCsisolated from healthy donor were incubated for 24 hours with CD20 TDB atindicated concentration. Reported cell killing was calculated asdescribed below.

FIG. 56I is a set of graphs showing that the extent of B cell killingwithin 24 hours by CD20 TDB is comparable or higher than B cell killingby CD19-TDB or CD22-TDB (top panel) or CD79a or CD79b (bottom panel).For autologous B cell killing, 200,000 PBMCs isolated from healthy donorwere incubated with 40,000 BJAB cells for 24 hours with CD20, CD19,CD22, CD79a, or CD 79b TDB at the indicated concentration. Reported cellkilling was calculated as described below.

FIG. 57A is a series of graphs showing the relative expression valuesfor human CD3ε detected in CD4+ T cells (left panel) and CD8+ T cells(center panel); and human CD20 in CD19+ B cells (right panel) detectedin mouse (mu) or human (hu) PBMCs as measured by FACS. Mouse PBMCs werederived from blood of double transgenic huCD3/huCD20 mice; human PBMCswere derived from healthy donor blood.

FIG. 57B is a graph showing that CD20 TDB cannot engage murine T cellsto deplete B cells without human CD3 expression in human CD20 transgenicmice. huCD20 transgenic mice or huCD20/CD3 double transgenic mice weretreated once intravenously with antibodies as indicated (10 mg/kg forrituximab, 0.5 mg/kg for CD20 TDB and HER2 TDB). Mouse spleens werecollected at D7 (7 days after antibody treatment). Anti-human CD20antibody rituximab is used as a positive control. CD3/HER2 TDB used asnegative, isotype control.

FIG. 57C is a graph showing that CD20 TDB is able to engage murine Tcells expressing huCD3 in human CD3/CD20 double transgenic mice topotently deplete murine B cells expressing huCD20. huCD20 transgenicmice or huCD20/CD3 double transgenic mice were treated onceintravenously with antibodies as indicated (10 mg/kg for rituximab, 0.5mg/kg for CD20 TDB and HER2 TDB). Mouse spleens were collected at D7 (7days after antibody treatment). CD3/HER2 TDB used as negative, isotypecontrol.

FIG. 58A is a series of graphs of a time-course study showing thattreatment with CD20 TDB resulted in sustained B cell depletion up to D15(15 days after dosing). huCD20/huCD3 double transgenic mice were treatedonce intravenously with various doses of CD20 TDB. Mouse blood (D1, D8,and D15) was collected.

FIG. 58B is a graph showing that near complete B cell depletion in mousespleens was only achieved at D7 after a single dose of 0.5 mg/kg, whilea lower dose of 0.05 mg/kg only resulted in spleen B cell depletionpartially. huCD20/CD3 double transgenic mice were treated onceintravenously with various dose of CD20 TDB. Spleens (D7) werecollected.

FIG. 58C is a graph showing that robust B cell depletion at D7 isobserved in circulation of double transgenic huCD3/huCD20 mice treatedwith CD20 TDB. huCD20/huCD3 double transgenic mice were treated onceintravenously with 0.5 mg/kg of CD20 TDB. Blood was collected at D0-5min (5 minutes after treatment), D0-2h, D0-8h, D1, D2, D3, and D7. Bcells expressing huCD20 were measured by FACS.

FIG. 58D is a series of graphs showing T cell activation in doubletransgenic huCD3/huCD20 mice treated with a CD20 TDB. Treated doubletransgenic huCD3/huCD20 mice exhibited up to an 80% increase in humanCD3ε expressing CD8+ T cell count at 2 hours post-CD20 TDB treatment,which returned to baseline level by D2 and D7 (top panel). Similarly,human CD3ε expressing CD4+ T cells increased by 80% 2 hours aftertreatment with CD20 TDB and subsequently returned to baseline level byD2. Double transgenic huCD3/huCD20 mice were treated once intravenouslywith 0.5 mg/kg of CD20 TDB. Blood was collected at D0-5 min (5 minutesafter treatment), D0-2h, D0-8h, D1, D2, D3, and D7. CD4+ and CD8+ Tcells expressing CD3ε were measured by FACS.

FIG. 59A is a series of flow cytometry graphs showing that CD20 TDBdepletes marginal zone B cells (MZB) as efficiently as follicular Bcells (FOB) after administration of TDB to double transgenichuCD3/huCD20 mice. Two double transgenic animals (left and right panels,respectively) were treated with vehicle (top panels) or a singleintravenous dose of 0.5 mg/kg TDB (bottom panels). Mouse spleens werecollected at D7 and analyzed by FACS.

FIG. 59B-59E is a series of graphs showing that CD20 TDB depletesmarginal zone B cells (MZB) (B) as efficiently as follicular B cells(FOB) (C) after a single intravenous dose of 0.5 mg/kg TDB, along withactivation of CD8+ T cells (D) and proliferation of CD8+ T cells (E) inthe spleen at the indicated time points. Mouse spleens were collected atD1, D2, D3, D5, D7, and D14.

FIG. 60A is a graph showing that humanized NSG mice treated with 3weekly doses of CD20 TDB at 0.5 mg/kg (repeat dose setting) exhibiteddepleted B cell levels in blood at D7, with almost no B cells detectedat D21. Humanized NSG mice were treated with 3 doses of 0.5 mg/kg CD20TDB weekly intravenously. Blood was collected at D-5 (5 days beforetreatment), D7, D14, and D21. Murine B cell counts in blood weremeasured by FACS.

FIG. 60B is a graph showing that robust B cell depletion at D21 isobserved in spleens of humanized NSG mice treated with CD20 TDB.Humanized NSG mice were treated with 3 doses of 0.5 mg/kg CD20 TDBweekly via intravenously. Spleens were collected at D21. Murine B cellcounts in spleen were measured by FACS.

FIG. 60C is a series of flow cytometry graphs showing that huCD8+ Tcells proliferate and huCD19+ B cells are depleted 7 days followingtreatment (D7) of humanized NSG mice with CD20 TDB. Humanized NSG micewere treated with vehicle or 0.5 mg/kg CD20 TDB (2H7v16/UCHT1v9). Thespleens of control and CD20 TDB treated humanized NSG mice werecollected on D7. B cells expressing huCD19 and T cells expressing huCD8were measured by FACS.

FIG. 60D is a graph showing that humanized NSG mice treated with 3weekly doses of CD20 TDB at 0.5 mg/kg (repeat dose setting) exhibited anup to 10-fold increase in CD8+ T cell count at D7, which returned tobaseline level or lower by D14 and D21. Humanized NSG mice were treatedwith 3 doses of 0.5 mg/kg CD20 TDB weekly via iv. Blood was collected atD-5 (5 days before treatment), D7, D14, and D21. Murine CD8+ T cellcounts in blood, and T cell activation was measured by FACS.

FIG. 60E is a series of flow cytometry graphs showing the baselinelevels of huCD20+ B cells (center panels) and huCD8+ and huCD4+ T cells(right panels) from 2 humanized NSG mice as measured by FACS.

FIG. 60F is a series of graphs showing the levels of cell surfaceexpression of huCD3ε and CD20 expression on CD19+ B cells (left), CD8+ Tcells (center), and CD4+ T cells (right) as detected by FACS.

FIG. 61A is a graph showing that CD20 TDB is potent in killing CLL Bcells with autologous T cells. 200,000 PBMCs were incubated with variousconcentration of CD20 TDB for 48 hours in RPMI media supplemented with10% FBS. FIG. 61B is a graph showing that CD20 TDB is potent in inducingactivation of autologous T cells in the presence of CLL B cells. 200,000PBMCs were incubated with various concentration of CD20 TDB for 48 hoursin RPMI media supplemented with 10% FBS.

FIG. 61C is a set of graphs showing that T cell count is highlycorrelative with killing of CLL B cells ex vivo. 200,000 PBMCs wereincubated with 1000 ng/ml CD20 TDB for 48 hours, either alone or withadded CD8+ T cells purified from healthy donor. The percentage ofCD19+CD5+ B cells and CD8+ T cells in CLL PBMCs are 90/0.55 for sampleA1645, 76/3.5 for A1957, 87/0.63 for A1978, 69/1.3 for A1980. Cellkilling, Granzyme B induction, and T cell activation were measured byFACS as described below.

FIG. 62A is a set of graphs showing that T cell activation (left)following 0.1 mg/kg or 0.5 mg/kg dosages of CD20 TDB to NSG mice withengrafted CLL leukemia cells correlated with the potent depletion ofengrafted CLL B cells (right).

FIG. 62B is a set of immunohistochemistry images of spleen sections fromNSG mice with engrafted CLL leukemia cells, showing that few B cells aredetectable following CD20 TDB treatment. B cells and T cells wereengrafted in NSG mice as described below. Mice were treated onceintravenously with HER2 TDB, and rituximab at 0.5 mg/kg, CD20 TDB at 0.1and 0.5 mg/kg, and spleens were collected for FACS analysis 14 daysafter treatment.

FIG. 63 is a graph showing the fitted tumor volume over time of Bjabengrafted tumors of SCID mice for Group 1 (vehicle: 20 mMHistidine/acetate pH 5.5, 240 mM Sucrose, 0.02% Tween 20); Group 2 (CD20TDB: 2H7v114/UCHT1.v9; 0.5 mg/kg); Group 3 (vehicle: 20 mMHistidine/acetate pH 5.5, 240 mM Sucrose, 0.02% Tween 20, PBMC); andGroup 4 (CD20 TDB: CD20 2H7v114/CD3 UCHT1.v9; 0.5 mg/kg, PBMC). Effectorcells were PBMCs derived from healthy human donor. Mice were treatedonce per week for two weeks.

FIG. 64A is a graph showing the relative level of CD20 expression onBjab, NALM-6, SC-1, and OCI-LY 19 cells. B cells and T cells wereengrafted in NSG mice as described below. Mice were treated onceintravenously with HER2 TDB, and rituximab at 0.5 mg/kg, CD20 TDB at 0.1and 0.5 mg/kg, and spleens were collected for IHC analysis 14 days aftertreatment.

FIG. 64B is a graph showing that rituximab and CD20 TDB are comparablein their efficacy for killing Bjab cells in vitro, which express a highlevel of CD20 on their cell surface. PBMCs isolated from healthy donorwere depleted of B cells, and used as effector cells in the in vitrocell killing assay. 20,000 B cells and 200,000 effector cells wereincubated with various concentration of CD20 TDB or rituximab for 24hours. CD20 TDB expression was detected by FACS.

FIG. 64C is a graph showing that CD20 TDB, but not rituximab, is capableof killing NALM-6, SC-1, and OCI-LY 19 cells, which have relatively lowlevels of CD20 on their cell surface. PBMCs isolated from healthy donorwere depleted of B cells, and used as effector cells in the in vitrocell killing assay. 20,000 B cells and 200,000 effector cells wereincubated with various concentration of CD20 TDB or rituximab for 24hours. CD20 TDB expression was detected by FACS.

FIG. 64D is a graph showing B cell surface expression levels ofunblocked CD20 antigen as a function of the concentration ofRituximab-DANA as measured by FACS. CD20/CD3 double transgenic mice weretreated with a single dose of vehicle or Rituximab-DANA (10 mg/kg).Spleens were harvested 5 days post-treatment.

FIGS. 65A and 65B are graphs showing that CD20 TDB is active in killingB cells in vitro in the presence of high levels of rituximab (A) ordexamethasone (B). 200,000 PBMCs isolated from healthy donor were firstincubated with rituximab-DANA at indicated concentration for 1 hour,CD20 TDB were then added and incubated for 24 hours. For dexamethasoneassay, cells were pre-treated with 1 μM dexamethasone overnight prior toadding CD20 TDB. Cell killing were calculated as described below.

FIG. 66 is a set of graphs showing that CD20 TDB is active in depletingB cells in blood (left) and spleen (right) in mice pre-treated withrituximab-DANA. For single agent treatment, huCD20/CD3 double transgenicmice were treated once intravenously at the dose indicated; forcombination treatment, mice were first treated intravenously withrituximab-DANA, and CD20 TDB were injected intravenously 30 minuteslater. Blood were collected at D-7, D0-2h (2 hours after TDB treatment),and D7; spleens were collected at D7. B cell counts were measured byFACS as described below.

FIG. 67A is a set of graphs showing the B cell (left), CD4+ T cell(middle), and CD8+ T cell (right) count in blood samples from 3cynomolgus monkeys before and 7 days after treatment with a singleintravenous dose of 1 mg/kg CD20 TDB. Three cynomolgus monkeys weretreated once intravenously with 1 mg/kg CD20 TDB. Blood were collectedat D-7 (7 days prior to dosing), D0-4 hr (4 hours right after dosing),and D7.

FIG. 67B is a set of graphs showing B cell, CD4+ T cell, and CD8+ T celllevels in the spleen (left), mandibular lymph nodes (middle), andmesenteric lymph nodes (right) of 3 cynomolgus monkeys 7 days aftertreatment with a single intravenous dose of 1 mg/kg CD20 TDB. Threecynomolgus monkeys were treated once intravenously with 1 mg/kg CD20TDB. Blood were collected at D-7 (7 days prior to dosing), D0-4 hr (4hours right after dosing), and D7.

FIG. 67C is a set of graphs showing B cell, CD4+ T cell, and CD8+ T celllevels in the spleen (left), mandibular lymph nodes (middle), andmesenteric lymph nodes (right) of 3 cynomolgus monkeys prior totreatment with a single intravenous dose of 1 mg/kg CD20 TDB. Threecynomolgus monkeys were treated once intravenously with 1 mg/kg CD20TDB. Blood were collected at D-7 (7 days prior to dosing), D0-4 hr (4hours right after dosing), and D7.

FIG. 67D is a set of graphs showing the baseline levels of B cells andCD4+ and CD8+ T cells as a percentage of total lymphocytes detected inthe spleen (left) and the mandibular lymph nodes (right) in vehiclecontrol-treated animals.

FIG. 68A is a set of graphs showing the CD20 TDB serum concentrationfrom collected blood and serum samples from four cynomolgus monkeys weretreated 4-times weekly with 1 mg/kg CD20 TDB via intraveneousadministration.

FIG. 68B is a set of graphs showing the CD20 TDB concentration fromserum samples collected from animals described in FIGS. 65 and 66A.Mean±s.d. were plotted.

FIG. 69A is histogram showing the expression of PD-L1 expression onA20-huCD20 cells from A20-huCD20 syngeneic Balb/C mice, as assessed byflow cytometry.

FIG. 69B is a graph showing the relative tumor volume over time forGroup 1 (vehicle); Group 2 (CD20 TDB at 0.5 mg/kg); Group 3 (anti-PD-L1antibody at 10 mg/kg); and Group 4 (CD20 TDB at 0.5 mg/kg+ anti-PD-L1antibody).

FIG. 70 is a graph showing the binding curves for each of the threetested FcRH5 TDBs tested for in vitro binding to CD8+CD3-expressing Tcells.

FIG. 71A is a graph showing the percentage of MOLP-2 target cell killingas a function of FcRH5 TDB concentration, with CD8+ T cells purifiedfrom human PBMCs from Donor #1.

FIG. 71B is a graph showing the percentage of MOLP-2 target cell killingas a function of FcRH5 TDB concentration, with CD8+ T cells purifiedfrom human PBMCs from Donor #2.

FIG. 72A is a graph showing the percentage of CD8+CD69+ T cells as afunction of FcRH5 TDB concentration, as assessed by FACS analysis.Target cells were MOLP-2, and CD8+ T cells were purified from Donor #1.

FIG. 72B is a graph showing the percentage of CD8+CD107a+ T cells as afunction of FcRH5 TDB concentration, as assessed by FACS analysis.Target cells were MOLP-2, and CD8+ T cells were purified from Donor #1.

FIG. 72C is a graph showing the percentage of CD8+CD69+ T cells as afunction of FcRH5 TDB concentration, as assessed by FACS analysis.Target cells were MOLP-2, and CD8+ T cells were purified from Donor #2.

FIG. 72D is a graph showing the percentage of CD8+CD107a+ T cells as afunction of FcRH5 TDB concentration, as assessed by FACS analysis.Target cells were MOLP-2, and CD8+ T cells were purified from Donor #2.

FIG. 73 is a set of graphs showing the binding curves for each of thethree HER2 TDBs tested for in vitro binding to Her2-expressing SKBR3cells (top) and CD8+CD3-expressing T cells (bottom).

FIG. 74A is a graph showing the binding curves for trastuzumab(bivalent), trastuzumab (Fab), and HER2 TDB (UCHT1v9/hu4D5) (bispecific)for in vitro binding to Her2-expressing SKBR3 cells.

FIG. 74B is a graph showing the percentage of viable SKBR3 cells as afunction of for trastuzumab (bivalent), trastuzumab (Fab), and HER2 TDB(UCHT1v9/hu4D5) (bispecific) concentration, as assessed by CELLTITERGLO®Luminescent Cell Viability Assay.

FIG. 74C is a graph showing the percentage of SKBR target cell killingsmediated by antibody-dependent cell-mediated cytotoxicity (ADCC) in thepresence of trastuzumab (T-mab), trastuzumab produced in E. coli (T-mabE. coli), and HER2 TDB (UCHT1v9/hu4D5), as assessed by lactatedehydrogenase (LDH) release from lysed cells.

FIG. 75 is a graph showing the percentage of SKBR3 target cell killingas a function of HER2 TDB (hu4D5-TDB, hu4D5.91A-TDB, andhu4D5.Y100A-TDB) concentration.

FIG. 76A is a series of panels. The top panel is a rendering of thecrystal structure of the HER2 extracellular domain (ECD) bound by hu4D5Fab (Trastuzumab), 2C4 Fab (Pertuzumab), and 7C2. The bottom panel is aribbon structure of the CD3ε bound by 2C11, 38E4v1, and 40G5c.

FIG. 76B is a table indicating the binding affinities, represented bythe dissociation constant K_(D) (nM), of HER2-TDB for three differentHER2 arms: hu4D5, 2C4, and 7C2. The bottom right panel is a tableindicating the binding affinities, represented by the dissociationconstant K_(D) (nM), of HER2-TDB for three different CD3ε arms: 38E4v1,40G5c, and 2C11.

FIG. 76C is a graph showing the percentage of HER2-expressing MCF7target cell killing as a function of HER2-TDB (hu4D5-TDB, 2C4-TDB, and7C2-TDB) concentration. Cytotoxicity was measured by the release oflactate dehydrogenase (LDH).

FIG. 77 is a graph showing the HER2 hu4D5 and 2C4 arms are potentmediators of cell killing as shown by the maximum percentage of SKBR3target cell killing achieved by treatment with the following HER2-TDBvariants: hu4D5-38E4v1, hu4D5-40G5c, 2C4-38E4v1, 2C4-40G5c, 7C2-38E4v1,and 7C2-40G5c.

FIG. 78 is a series of graphs showing the potency of variants of theHER2-TDB in killing HER2-expressing SKBR3 (left) and HER2-expressingMCF7 (right) cell lines in a dose-dependent manner, with EC50 values oftarget cell killing (pM).

FIG. 79 is a series of graphs showing the percentage of HER2-expressingSKBR3 target cell killing for various TDBs with HER2 arms (hu4D5, 2C4,and 7C2) paired with high affinity (38E4v1) or low affinity (40G5c) CD3arms as a function of TDB concentration (ng/mL).

FIG. 80 is a series of panels. The panel on the left is showing thepotency of variants of the HER2-TDB (hu4D5-38E4v1, 2C4-38E4v1,7C2-38E4v1; hu4D5-40G5c, 2C4-40G5c, 7C2-40G5c) in killingHER2-expressing SKBR3 and HER2-expressing MCF7 cell lines in a dosedependent manner, with EC50 values of target cell killing (pM). Thepanel on the right is a table with the ratio of the EC50 of the givenHER2-TDB variants in MCF7 versus SKBR3 target cells for threeexperiments.

FIG. 81 is a series of panels. The top panel is showing a table listingthe variants of the hu4D5 HER2 arm (hu4D5v7, hu4D5v5, hu4D5v10,hu4D5v31, hu4D5.Y100A) for HER2-TDB (40G5c CD3 arm) and thecorresponding EC50 (ng/mL) for SKBR3 target cell killing, HER2 bindingaffinity (K_(D), nM) in addition to the ratio of the HER2 bindingaffinity K_(D) and SKBR3 target cell killing EC50 for the hu4D5 variantsrelative to hu4D5. The bottom panel is a graph showing the correlationbetween the SKBR3 EC50 ratio for the hu4D5 HER2-TDB variants (hu4D5,hu4D5v7, hu4D5v5, hu4D5v10, and hu4D5v31) and the relative K_(D) ratiofor the hu4D5 HER2-TDB variants.

FIG. 82 is a series of graphs showing the percentage of SKBR3 and MCF7target cell killing as a function of the concentration of the followingHER2-TDB variants: hu4D5-40G5c (top left), hu4D5v7-40G5c (top center),hu4D5v5-40G5c (top right), hu4D5v10-40G5c (bottom left), hu4D5v31-40G5c(bottom center), hu4D5.Y100A-40G5c (bottom right).

FIG. 83 is a series of graphs. The graph on the left is showing thepercentage of target cell killing as a function of the concentration(μg/mL) of HER2 blocking bivalent monospecific antibodies specific forthe designated HER2 arm of the HER2-TDB. (HER2 blocking antibodies:bivalent monospecific antibodies to hu4D5, 2C4, and 7C2. HER2-TDBs:hu4D5-40G5c, 2C4-40G5c, and 7C2-38E4v1 at fixed concentration: 10ng/mL.) The graph on the right is showing the percentage of viable cellsas a function of the concentration of the HER2 antibody (hu4D5)trastuzumab in the presence and absence of the HER2-TDB hu4D5-40G5c.

FIG. 84 is a series of panels. The top panel is a table providing thereactivity of variants of the HER2 arm with HER2 as measured by variousbinding assays in addition to the reactivity of the HER2 clones with thehu4D5 antibody trastuzumab. The bottom panel is a graph showing thepercentage of target cell killing as a function of the concentration(pM) of HER2 bispecific Fab for the given clones (hu4D5, 3H4, and 2H11).EC50 values are given for each clone in pM.

FIG. 85 is a table providing affinity and reactivity information for thevariants of the HER2-TDB CD3 arm (38E4v1, 38E4, SP34, 40G5c, and 2C11).

FIG. 86 is a graph showing HER2-expressing CT26 target cell killing as afunction of concentration (ng/mL) of variants of HER2-TDB (hu4D5-2C11,hu4D5-SP34, 7C2-2C11, and 2C4-2C11). Effector cells: CD3-TG derived Tcells

FIG. 87A is a graph showing tumor volume (mm³) measured over time (0-5days) in animals treated with vehicle or HER2-TDB (0.5 mg/kg).

FIG. 87B is a series of graphs. The top left graph is showing thepercentage of peripheral CD45+ cells per 5 cells detected on day 6 postvehicle or HER2-TDB (0.5 mg/kg) treatment. The top right graph isshowing the percentage of peripheral CD45+ cells that are CD8+ cellsdetected on day 6 post vehicle or HER2-TDB (0.5 mg/kg) treatment. Thebottom left graph is showing the percentage of peripheral CD45+ cellsthat are CD4+ detected on day 6 post vehicle or HER2-TDB (0.5 mg/kg)treatment. The bottom right graph is showing the percentage ofperipheral CD8+ cells that are IFN+ detected on day 6 post vehicle orHER2-TDB (0.5 mg/kg) treatment.

FIG. 88A is a series of graphs. The top graph is showing a waterfallplot of the percent change in tumor volume in animals treated withvehicle or HER2-TDB variant (hu4D5-SP34 or hu4D5-2C11; 0.5 mg/kg; IV,weekly, 5 weeks). The bottom graph is showing a waterfall plot of thepercent change in tumor volume in animals treated with HER2-TDB variant(2C4-38E4; 0.5 mg/kg; IV, weekly, 5 weeks).

FIG. 88B is a series of graphs. The top graph is showing tumor volume asa percent of baseline volume as a function of time (days) for vehicle orHER2-TDB (hu4D5-SP34) treated animals. The bottom graph is showing tumorvolume as a percent of baseline volume as a function of time (days) forvehicle or HER2-TDB (hu4D5-2C11) treated animals. (HER2-TDB: 0.5 mg/kg;IV, weekly, 5 weeks).

FIG. 89 is a graph showing the percentage of CD8+CD107a+ T cells as afunction of HER2 TDB (hu4D5-TDB, hu4D5.91A-TDB, and hu4D5.Y100A-TDB)concentration hu4D5, as assessed by FACS analysis. Target cells wereSKBR3 cells; effector cells were CD8+ T cells; effector cell:target cellratio=3:1.

FIG. 90A is a graph showing the percentage of SKBR3 target cell killingas a function of HER2 TDB (UCHT1v9/hu4D5 and SP34/hu4D5) concentration.

FIG. 90B is a graph showing the percentage of SKBR3 target cell killingas a function of HER2 TDB (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5)concentration.

FIG. 90C is a graph showing the percentage of SKBR3 target cell killingas a function of HER2 TDB (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5)concentration.

FIG. 91A is a graph showing the binding curve for each of the threeHER2-TDBs (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5) tested for in vitrobinding to CD8+CD3-expressing T cells as assessed by FACS analysis.

FIG. 91B is a graph showing the percentage of CD8+CD69+ T cells as afunction of HER2-TDB (SP34/hu4D5, 38E4c/hu4D5, and 40G5c/hu4D5)concentration.

FIG. 92A is a graph showing the binding curve for the two HER2 TDBs(38E4c/hu4D5 and 38E4/hu4D5) tested for in vitro binding toCD8+CD3-expressing T cells, as assessed by FACS analysis.

FIG. 92B is a graph showing the binding curve for the two HER2 TDBs(38E4c/hu4D5 and 38E4/hu4D5) tested for in vitro binding toHer2-expressing SKBR3 cells, as assessed by FACS analysis.

FIG. 92C is a graph showing the percentage of SKBR3 target cell killingas a function of HER2 TDB (38E4c/hu4D5 and 38E4/hu4D5) concentration asassessed by FACS analysis. Effector cells were human CD8+ T cells;effector cell:target cell ratio=3:1.

FIG. 92D is a graph showing the percentage of CD8+CD69+ T cells as afunction of HER2-TDB (38E4c/hu4D5 and 38E4/hu4D5) concentration.

FIG. 93A is a graph showing the percentage of CD8+CD69+GranzymeB+ Tcells as a function of HER2 TDB (UCHT1v9/hu4D5) concentration, asassessed by FACS analysis. Target cells were SKBR3 cells; effector cellswere CD8+ T cells; effector cell:target cell ratio=3:1.

FIG. 93B is a series of graphs showing HER2 TDB (UCHT1v9/hu4D5) Tcell-mediated target cell granule exocytosis detected by ELISA forperforin and granzymes A and B, and the percentage of target cellkilling as assessed by LDH release. Target cells were SKBR3 cells;effector cells were PBMCs; effector cell:target cell ratio=30:1.

FIG. 93C is a series of graphs showing HER2 TDB (UCHT1v9/hu4D5) Tcell-mediated target cell apoptosis as measured by caspase-3 andcaspase-7 activities in a CASPASE-GLO® 3/7 assay, apoptosis in a CellDeath Detection ELISA^(plus) assay, and LDH release. Target cells wereSKBR3 cells; effector cells were PBMCs; effector cell:target cellratio=10:1.

FIG. 93D is the image of a Western blot (top) showing the expression ofHer2 in 3T3 transfected cells and a graph (bottom) showing thepercentage of target cell killing by activated T cells as a function ofHER2 TDB (UCHT1v9/hu4D5) concentration as measured by LDH release.Target cells were 3T3-Vector and 3T3-HER2; effector cells were PBMCs;effector cell:target cell ratio=10:1.

FIG. 93E is a graph showing the percentage of BT474 target cell killingas a function of HER2 TDB (UCHT1v9/hu4D5) concentration in the presenceof trastuzumab Fab (T-Fab) or soluble HER2 extracellular domain (ECD) asassessed by LDH release. Effector cells were CD8+ T cells; effectorcell:target cell ratio=5:1.

FIG. 93F is a graph showing the percentage of SKBR3 target cell killingas a function of HER2 TDB (UCHT1v9/hu4D5) concentration following thedepletion of CD3+ cells from the PBMC effector cell population. Effectorcell:target cell ratio=20:1.

FIG. 94A is a series of graphs showing the percentage of CD8+CD69+ Tcells (left) and CD8+CD107a+ T cells (middle) as a function of HER2 TDB(UCHT1v9/hu4D5) concentration, as assessed by FACS analysis, and thepercentage of SKBR3 target cell killing as a function of HER2 TDB(UCHT1v9/hu4D5) concentration (right). Target cells were SKBR3 cells;effector cells were CD8+ T cells; effector cell:target cell ratio=3:1.

FIG. 94B is a series of graphs showing the percentage of BT474 targetcell killing as a function of HER2 TDB (UCHT1v9/hu4D5) concentration(left) and the percentage of CD8+CD69+GranzymeB+ T cells as a functionof HER2 TDB (UCHT1v9/hu4D5) concentration (right), as assessed by FACSanalysis. Target cells were BT474 cells; effector cells were CD8+ Tcells; effector cell:target cell ratio as indicated.

FIG. 95A is a series of histograms showing the expression of CFSE inCD8+ T cells in the presence of SKBR3 target cells and/or HER2 TDB(UCHT1v9/hu4D5).

FIG. 95B is a graph showing the fold change in CD8+ cell number as afunction of time following incubation with SKBR3 target cells and HER2TDB (UCHT1v9/hu4D5), as assessed by FACS analysis.

FIG. 95C are a series of graphs showing the fold change in CD8+ cellnumber as a function of time following incubation with SKBR3 targetcells, HER2 TDB (UCHT1v9/hu4D5), and 20 ng/ml IL-2, as assessed by FACSanalysis.

FIG. 96A is an image of a Western blot showing the expression level ofHer2 in a panel of human tumor cell lines.

FIG. 96B is a graph showing the percentage of target cell killing as afunction of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by LDHrelease. Target cells were BJAB, MDA435, MDA231, MCF7, MDA453, SKBR3,and BT474; effector cells were PBMCs; effector cell:target cellratio=25:1.

FIG. 96C is a graph showing the percentage of target cell killing as afunction of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by FACSanalysis. Target cells were MCF7 and SKBR3; effector cells were PBMCs;effector cell:target cell ratio=20:1.

FIG. 96D is a graph showing the percentage of target cell killing as afunction of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by FACSanalysis. Target cells were BJAB and SKBR3; effector cells were PBMCs;effector cell:target cell ratio=20:1.

FIG. 96E is a table displaying the HER2 copy number for a panel oftarget cells and for each, the HER2 TDB EC50 and percentage of HER2occupancy at that concentration. Target cells are MDA435, MDA231, MCF7,MDA453, BT474, and SKBR3.

FIG. 97A is a graph showing the percentage of target cell killing as afunction of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by LDHrelease. Target cells were SKBR3, HCC1569, KPL4, HCC202, JIMT1, andCALU3; effector cells were PBMCs; effector cell:target cell ratio=10:1.

FIG. 97B is a graph showing the percentage of viable target cells as afunction of trastuzumab emtansine (T-DM1) concentration as assessed byCELLTITERGLO® Luminescent Cell Viability Assay. Target cells wereparental BT474-M1 and T-DM1 resistant BT474-M1; effector cells were CD8+T cells; effector cell:target cell ratio=3:1.

FIG. 97C is a graph showing the percentage of viable target cells as afunction of HER2 TDB (UCHT1v9/hu4D5) concentration as assessed by FACSanalysis. Target cells were parental BT474-M1 and T-DM1 resistantBT474-M1; effector cells were CD8+ T cells; effector cell:target cellratio=3:1.

FIG. 98 is a graph and a table showing the pharmacokinetics (PK) of HER2TDB (UCHT1v9/hu4D5) in Sprague-Dawley rats as assessed by ELISA.

FIG. 99A is a graph showing the relative tumor volume over time forGroup 1 (Vehicle at 0.5 mg/kg); Group 2 (PBMC(1)+vehicle at 0.5 mg/kg);Group 3 (PBMC(1)+HER2 TDB (UCHT1v9/hu4D5) at 0.5 mg/kg); Group 4(PBMC(2)+vehicle at 0.5 mg/kg); and Group 5 (PBMC(2)+HER2 TDB(UCHT1v9/hu4D5) at 0.5 mg/kg).

FIG. 99B is a graph showing the percentage of change in tumor volumeover time for Group 1 (Vehicle at 0.5 mg/kg); and Group 2 (HER2 TDB(hu4D5/2C11) at 0.5 mg/kg).

FIG. 99C is a histogram showing the relative percentage of change intumor volume over time for Group 1 (Vehicle at 0.5 mg/kg); and Group 2(HER2 TDB (hu4D5/2C11) at 0.5 mg/kg).

FIG. 99D is a graph showing the relative tumor volume over time forGroup 1 (Vehicle at 0.5 mg/kg); and Group 2 (HER2 TDB (hu4D5/2C11) at0.5 mg/kg). Responders included tumors that were greater than 1000 mm³at the start of treatment.

FIG. 99E is a graph showing the percentage of change in tumor volumeover time for Group 1 (CD3-arm control HER2 TDB (hu4D5/SP34) at 0.5mg/kg); and Group 2 (control TDB (2C11) at 0.5 mg/kg).

FIG. 99F is a graph showing the relative tumor volume over time forGroup 1 (Vehicle at 0.5 mg/kg); and Group 2 (HER2 TDB (hu4D5/SP34) at0.5 mg/kg).

FIG. 99G is a graph showing the relative tumor volume over time forGroup 1 (Vehicle at 0.5 mg/kg); Group 2 (HER2 TDB (hu4D5/2C11) at 0.5mg/kg); Group 3 (control TDB (2C11) at 0.5 mg/kg); and Group 4 (T-DM1 at15 mg/kg).

FIG. 100A is a graph showing the relative tumor volume over time forGroup 1 (Untreated); Group 2 (HER2 TDB (UCHT1v9/hu4D5) at 0.5 mg/kg).

FIG. 100B is a graph showing the relative tumor volume over time forGroup 1 (Vehicle at 0.5 mg/kg); Group 2 (PBMC(3)+Vehicle at 0.5 mg/kg);and Group 3 (PBMC(3)+control TDB (2C11) at 0.5 mg/kg).

FIG. 101A is a graph showing the binding affinity for the CD3-UCHT1antibody tested for in vitro binding to human CD3 on human T cells, CD3TG T cells, and BALB/c T cells, as assessed by FACS analysis.

FIG. 101B is a graph showing the binding affinity for the CD3-2C11antibody tested for in vitro binding to mouse CD3 on CD3 TG T cells andBALB/c T cells, as assessed by FACS analysis.

FIG. 102A is a graph showing the percentage of CT26-HER2 target cellkilling as a function of HER2 TDB (UCHT1v9/hu4D5) concentration, asassessed by FACS analysis. Effector cells were human peripheral bloodisolated T cells, huCD3 transgenic splenic T cells, and BALB/c splenic Tcells.

FIG. 102B is a graph showing the percentage of CT26-HER2 target cellkilling as a function of HER2 TDB (hu4D5/2C11) concentration, asassessed by FACS analysis. Effector cells were human peripheral bloodisolated T cells, huCD3 transgenic splenic T cells, and BALB/c splenic Tcells.

FIG. 103 is a graph showing the relative tumor volume over time forGroup 1 (Vehicle at 0.5 mg/kg); and Group 2 (HER2 TDB (hu4D5/SP34) at0.5 mg/kg).

FIG. 104 a graph showing the binding curves for each of the three LYPD1TDBs tested for in vitro binding to CD8+CD3-expressing T cells.

FIG. 105 is a graph showing the percentage of OVCAR3.Luc target cellkilling as a function of LYPD1 TDB concentration.

FIG. 106 is a set of graphs showing the percentage of CD8+CD69+(left)and CD8+CD25+(right) T cells as a function of LYPD1 TDB concentration,as assessed by FACS analysis. Target cells were OVCAR3.Luc cells;effector cell:target cell ratio=3:1.

FIG. 107 shows the amino acid sequences of the light chain variabledomain (top) and heavy chain variable domain (bottom) of anti-RETantibody 41205.v6.

FIG. 108A is a graph showing tumor volume (mm³) as a function of time(days) for Group 1 (vehicle, qwx3, IV; n=9); Group 2 (CD20 TDB(2H7-mu2C11), 0.5 mg/kg, qwx3, IV; n=9); Group 3 (anti-PD1 (mu8F11DANA), 10 mg/kg, tiwx3, IP; n=9); and Group 4 (anti-PD1 (mu8F11 DANA),10 mg/kg, tiwx3, IP+CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, IV; n=9).

FIG. 108B is a graph showing tumor volume (mm³) as a function of time(days) for Group 1 (vehicle, qwx3, IV; n=9); Group 2 (CD20 TDB(2H7-mu2C11), 0.5 mg/kg, qwx3, IV; n=9); Group 3 (anti-PD1 (mu8F11DANA), 10 mg/kg, tiwx3, IP; n=9); and Group 4 (anti-PD1 (mu8F11 DANA),10 mg/kg, tiwx3, IP+CD20 TDB (2H7-mu2C11), 0.5 mg/kg, qwx3, IV; n=9).The bolded solid line represents the fitted tumor volume for thespecified group.

FIG. 109 is a table showing CD3 contacts for the hu38E4.v1/CD3ε complex.Hydrogen bonding between two side chains is represented by *; shadedcells represent reliable hydrogen bonding contacts; and bolded contactsare hydrogen bonds formed between side chains and main chain backbones.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION I. Definitions

The term “about” as used herein refers to the usual error range for therespective value readily known to the skilled person in this technicalfield. Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse.

An “acceptor human framework” for the purposes herein is a frameworkcomprising the amino acid sequence of a light chain variable domain (VL)framework or a heavy chain variable domain (VH) framework derived from ahuman immunoglobulin framework or a human consensus framework, asdefined below. An acceptor human framework “derived from” a humanimmunoglobulin framework or a human consensus framework may comprise thesame amino acid sequence thereof, or it may contain amino acid sequencechanges. In some embodiments, the number of amino acid changes are 10 orless, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less,3 or less, or 2 or less. In some embodiments, the VL acceptor humanframework is identical in sequence to the VL human immunoglobulinframework sequence or human consensus framework sequence.

“Affinity” refers to the strength of the sum total of noncovalentinteractions between a single binding site of a molecule (e.g., anantibody) and its binding partner (e.g., an antigen). Unless indicatedotherwise, as used herein, “binding affinity” refers to intrinsicbinding affinity which reflects a 1:1 interaction between members of abinding pair (e.g., antibody and antigen). The affinity of a molecule Xfor its partner Y can generally be represented by the dissociationconstant (Kd). Affinity can be measured by common methods known in theart, including those described herein. Specific illustrative andexemplary embodiments for measuring binding affinity are described inthe following.

An “affinity matured” antibody refers to an antibody with one or morealterations in one or more hypervariable regions (HVRs), compared to aparent antibody which does not possess such alterations, suchalterations resulting in an improvement in the affinity of the antibodyfor antigen.

The terms “anti-CD3 antibody” and “an antibody that binds to CD3” referto an antibody that is capable of binding CD3 with sufficient affinitysuch that the antibody is useful as a diagnostic and/or therapeuticagent in targeting CD3. In one embodiment, the extent of binding of ananti-CD3 antibody to an unrelated, non-CD3 protein is less than about10% of the binding of the antibody to CD3 as measured, e.g., by aradioimmunoassay (RIA). In certain embodiments, an antibody that bindsto CD3 has a dissociation constant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1nM, ≤0.1 nM, ≤0.01 nM, or ≤0.001 nM (e.g. 10⁻⁸ M or less, e.g. from 10⁻⁸M to 10⁻¹³ M, e.g., from 10⁻⁹ M to 10⁻¹³ M). In certain embodiments, ananti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3from different species.

The term “antibody” herein is used in the broadest sense and encompassesvarious antibody structures, including but not limited to monoclonalantibodies, polyclonal antibodies, multispecific antibodies (e.g.,bispecific antibodies), and antibody fragments so long as they exhibitthe desired antigen-binding activity.

An “antibody fragment” refers to a molecule other than an intactantibody that comprises a portion of an intact antibody that binds theantigen to which the intact antibody binds. Examples of antibodyfragments include but are not limited to Fv, Fab, Fab′, Fab′-SH,F(ab′)₂; diabodies; linear antibodies; single-chain antibody molecules(e.g. scFv); and multispecific antibodies formed from antibodyfragments.

By “binding domain” is meant a part of a compound or a molecule thatspecifically binds to a target epitope, antigen, ligand, or receptor.Binding domains include but are not limited to antibodies (e.g.,monoclonal, polyclonal, recombinant, humanized, and chimericantibodies), antibody fragments or portions thereof (e.g., Fabfragments, Fab′2, scFv antibodies, SMIP, domain antibodies, diabodies,minibodies, scFv-Fc, affibodies, nanobodies, and VH and/or VL domains ofantibodies), receptors, ligands, aptamers, and other molecules having anidentified binding partner.

A “chemotherapeutic agent” is a chemical compound useful in thetreatment of cancer. Examples of chemotherapeutic agents includealkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®);alkyl sulfonates such as busulfan, improsulfan and piposulfan;aziridines such as benzodopa, carboquone, meturedopa, and uredopa;ethylenimines and methylamelamines including altretamine,triethylenemelamine, triethylenephosphoramide,triethylenethiophosphoramide and trimethylomelamine; acetogenins(especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol(dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinicacid; a camptothecin (including the synthetic analogue topotecan(HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin,scopolectin, and 9-aminocamptothecin); bryostatin; callystatin; CC-1065(including its adozelesin, carzelesin and bizelesin syntheticanalogues); podophyllotoxin; podophyllinic acid; teniposide;cryptophycins (particularly cryptophycin 1 and cryptophycin 8);dolastatin; duocarmycin (including the synthetic analogues, KW-2189 andCB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin;nitrogen mustards such as chlorambucil, chlornaphazine,chlorophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,and ranimnustine; antibiotics such as the enediyne antibiotics (e.g.,calicheamicin, especially calicheamicin gamma1I and calicheamicinomegall (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33:183-186 (1994)); CDP323, an oral alpha-4 integrin inhibitor; dynemicin,including dynemicin A; an esperamicin; as well as neocarzinostatinchromophore and related chromoprotein enediyne antibiotic chromophores),aclacinomysins, actinomycin, authramycin, azaserine, bleomycins,cactinomycin, carabicin, caminomycin, carzinophilin, chromomycins,dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,doxorubicin (including ADRIAMYCIN®, morpholino-doxorubicin,cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HClliposome injection (DOXIL®), liposomal doxorubicin TLC D-99 (MYOCET®),peglylated liposomal doxorubicin (CAELYX®), and deoxydoxorubicin),epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such asmitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin,porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;anti-metabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur(UFTORAL®), capecitabine (XELODA®), an epothilone, and 5-fluorouracil(5-FU); combretastatin; folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine;androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil;amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids suchas maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol;nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone;2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS NaturalProducts, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium;tenuazonic acid; triaziquone; 2,2′,2′-trichlorotriethylamine;trichothecenes (especially T-2 toxin, verracurin A, roridin A andanguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); thiotepa; taxoid, e.g., paclitaxel (TAXOL®,Bristol-Myers Squibb Oncology, Princeton, N.J.), albumin-engineerednanoparticle formulation of paclitaxel (ABRAXANE™), and docetaxel(TAXOTERE®, Rhome-Poulene Rorer, Antony, France); chloranbucil;6-thioguanine; mercaptopurine; methotrexate; platinum agents such ascisplatin, oxaliplatin (e.g., ELOXATIN®), and carboplatin; vincas, whichprevent tubulin polymerization from forming microtubules, includingvinblastine (VELBAN®), vincristine (ONCOVIN®), vindesine (ELDISINE®,FILDESIN®), and vinorelbine (NAVELBINE®); etoposide (VP-16); ifosfamide;mitoxantrone; leucovorin; novantrone; edatrexate; daunomycin;aminopterin; ibandronate; topoisomerase inhibitor RFS 2000;difluoromethylornithine (DMFO); retinoids such as retinoic acid,including bexarotene (TARGRETIN®); bisphosphonates such as clodronate(for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095,zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®),pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®);troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisenseoligonucleotides, particularly those that inhibit expression of genes insignaling pathways implicated in aberrant cell proliferation, such as,for example, PKC-alpha, Raf, H-Ras, and epidermal growth factor receptor(EGF-R) (e.g., erlotinib (Tarceva™)); and VEGF-A that reduce cellproliferation; vaccines such as THERATOPE® vaccine and gene therapyvaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, andVAXID® vaccine; topoisomerase 1 inhibitor (e.g., LURTOTECAN®); rmRH(e.g., ABARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib,SUTENT®, Pfizer); perifosine, COX-2 inhibitor (e.g. celecoxib oretoricoxib), proteosome inhibitor (e.g. PS341); bortezomib (VELCADE®);CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitor such asoblimersen sodium (GENASENSE®); pixantrone; EGFR inhibitors; tyrosinekinase inhibitors; serine-threonine kinase inhibitors such as rapamycin(sirolimus, RAPAMUNE®); farnesyltransferase inhibitors such aslonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts,acids or derivatives of any of the above; as well as combinations of twoor more of the above such as CHOP, an abbreviation for a combinedtherapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone;and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin(ELOXATIN™) combined with 5-FU and leucovorin, and pharmaceuticallyacceptable salts, acids or derivatives of any of the above; as well ascombinations of two or more of the above.

Chemotherapeutic agents as defined herein include “anti-hormonal agents”or “endocrine therapeutics” which act to regulate, reduce, block, orinhibit the effects of hormones that can promote the growth of cancer.They may be hormones themselves, including, but not limited to:anti-estrogens and selective estrogen receptor modulators (SERMs),including, for example, tamoxifen (including NOLVADEX® tamoxifen),raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene,LY117018, onapristone, and FARESTON.cndot.toremifene; aromataseinhibitors that inhibit the enzyme aromatase, which regulates estrogenproduction in the adrenal glands, such as, for example, 4(5)-imidazoles,aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane,formestanie, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, andARIMIDEX® anastrozole; and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides,particularly those which inhibit expression of genes in signalingpathways implicated in abherant cell proliferation, such as, forexample, PKC-alpha, Raf and H-Ras; ribozymes such as a VEGF expressioninhibitor (e.g., ANGIOZYME® ribozyme) and a HER2 expression inhibitor;vaccines such as gene therapy vaccines, for example, ALLOVECTIN®vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; PROLEUKIN® rIL-2;LURTOTECAN® topoisomerase 1 inhibitor; ABARELIX® rmRH; Vinorelbine andEsperamicins (see U.S. Pat. No. 4,675,187), and pharmaceuticallyacceptable salts, acids or derivatives of any of the above; as well ascombinations of two or more of the above.

The term “chimeric” antibody refers to an antibody in which a portion ofthe heavy and/or light chain is derived from a particular source orspecies, while the remainder of the heavy and/or light chain is derivedfrom a different source or species.

The term “cluster of differentiation 3” or “CD3,” as used herein, refersto any native CD3 from any vertebrate source, including mammals such asprimates (e.g. humans) and rodents (e.g., mice and rats), unlessotherwise indicated, including, for example, CD3ε, CD3γ, CD3α, and CD3βchains. The term encompasses “full-length,” unprocessed CD3 (e.g.,unprocessed or unmodified CD3ε or CD3γ), as well as any form of CD3 thatresults from processing in the cell. The term also encompasses naturallyoccurring variants of CD3, including, for example, splice variants orallelic variants. CD3 includes, for example, human CD3ε protein (NCBIRefSeq No. NP_000724), which is 207 amino acids in length, and humanCD3γ protein (NCBI RefSeq No. NP_000064), which is 182 amino acids inlength.

The “class” of an antibody refers to the type of constant domain orconstant region possessed by its heavy chain. There are five majorclasses of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of thesemay be further divided into subclasses (isotypes), e.g., IgG₁, IgG₂,IgG₃, IgG₄, IgA₁, and IgA₂. The heavy chain constant domains thatcorrespond to the different classes of immunoglobulins are called α, δ,ε, γ, and μ, respectively.

It is understood that aspects and embodiments of the invention describedherein include “comprising,” “consisting,” and “consisting essentiallyof” aspects and embodiments.

The term “cytotoxic agent” as used herein refers to a substance thatinhibits or prevents a cellular function and/or causes cell death ordestruction. Cytotoxic agents include, but are not limited to,radioactive isotopes (e.g., At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³,Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); chemotherapeuticagents or drugs (e.g., methotrexate, adriamicin, vinca alkaloids(vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycinC, chlorambucil, daunorubicin or other intercalating agents); growthinhibitory agents; enzymes and fragments thereof such as nucleolyticenzymes; antibiotics; toxins such as small molecule toxins orenzymatically active toxins of bacterial, fungal, plant or animalorigin, including fragments and/or variants thereof; and the variousantitumor or anticancer agents disclosed below.

A “disorder” is any condition that would benefit from treatmentincluding, but not limited to, chronic and acute disorders or diseasesincluding those pathological conditions which predispose the mammal tothe disorder in question.

The terms “cell proliferative disorder” and “proliferative disorder”refer to disorders that are associated with some degree of abnormal cellproliferation. In one embodiment, the cell proliferative disorder iscancer. In one embodiment, the cell proliferative disorder is a tumor.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. Examples of cancer include but are not limitedto, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies. More particular examples of such cancers include, but notlimited to, squamous cell cancer (e.g., epithelial squamous cellcancer), lung cancer including small-cell lung cancer, non-small celllung cancer, adenocarcinoma of the lung and squamous carcinoma of thelung, cancer of the peritoneum, hepatocellular cancer, gastric orstomach cancer including gastrointestinal cancer and gastrointestinalstromal cancer, pancreatic cancer, glioblastoma, cervical cancer,ovarian cancer, liver cancer, bladder cancer, cancer of the urinarytract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectalcancer, endometrial or uterine carcinoma, salivary gland carcinoma,kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer,hepatic carcinoma, anal carcinoma, penile carcinoma, melanoma,superficial spreading melanoma, lentigo maligna melanoma, acrallentiginous melanomas, nodular melanomas, multiple myeloma and B-celllymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL);small lymphocytic (SL) NHL; intermediate grade/follicular NHL;intermediate grade diffuse NHL; high grade immunoblastic NHL; high gradelymphoblastic NHL; high grade small non-cleaved cell NHL; bulky diseaseNHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom'sMacroglobulinemia); chronic lymphocytic leukemia (CLL); acutelymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloblasticleukemia; and post-transplant lymphoproliferative disorder (PTLD), aswell as abnormal vascular proliferation associated with phakomatoses,edema (such as that associated with brain tumors), Meigs' syndrome,brain, as well as head and neck cancer, and associated metastases. Incertain embodiments, cancers that are amenable to treatment by theantibodies of the invention include breast cancer, colorectal cancer,rectal cancer, non-small cell lung cancer, glioblastoma, non-Hodgkinslymphoma (NHL), renal cell cancer, prostate cancer, liver cancer,pancreatic cancer, soft-tissue sarcoma, kaposi's sarcoma, carcinoidcarcinoma, head and neck cancer, ovarian cancer, mesothelioma, andmultiple myeloma. In some embodiments, the cancer is selected from:small cell lung cancer, gliblastoma, neuroblastomas, melanoma, breastcarcinoma, gastric cancer, colorectal cancer (CRC), and hepatocellularcarcinoma. Yet, in some embodiments, the cancer is selected from:non-small cell lung cancer, colorectal cancer, glioblastoma and breastcarcinoma, including metastatic forms of those cancers. In otherembodiments, the cancer is selected from a class of mature B-Cellcancers excluding Hodgkin's Lymphoma but including germinal-centerB-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, follicularlymphoma (FL), mantle cell lymphoma (MCL), acute myeloid leukemia (AML),chronic lymphoid leukemia (CLL), marginal zone lymphoma (MZL), smalllymphocytic leukemia (SLL), lymphoplasmacytic lymphoma (LL), Waldenstrommacroglobulinemia (WM), central nervous system lymphoma (CNSL),Burkitt's lymphoma (BL), B-cell prolymphocytic leukemia, Splenicmarginal zone lymphoma, Hairy cell leukemia, Splenic lymphoma/leukemia,unclassifiable, Splenic diffuse red pulp small B-cell lymphoma, Hairycell leukemia variant, Waldenström macroglobulinemia, Heavy chaindiseases, a Heavy chain disease, γ Heavy chain disease, μ Heavy chaindisease, Plasma cell myeloma, Solitary plasmacytoma of bone,Extraosseous plasmacytoma, Extranodal marginal zone lymphoma ofmucosa-associated lymphoid tissue (MALT lymphoma), Nodal marginal zonelymphoma, Pediatric nodal marginal zone lymphoma, Pediatric follicularlymphoma, Primary cutaneous follicle centre lymphoma, T-cell/histiocyterich large B-cell lymphoma, Primary DLBCL of the CNS, Primary cutaneousDLBCL, leg type, EBV-positive DLBCL of the elderly, DLBCL associatedwith chronic inflammation, Lymphomatoid granulomatosis, Primarymediastinal (thymic) large B-cell lymphoma, Intravascular large B-celllymphoma, ALK-positive large B-cell lymphoma, Plasmablastic lymphoma,Large B-cell lymphoma arising in HHV8-associated multicentric Castlemandisease, Primary effusion lymphoma: B-cell lymphoma, unclassifiable,with features intermediate between diffuse large B-cell lymphoma andBurkitt lymphoma, and B-cell lymphoma, unclassifiable, with featuresintermediate between diffuse large B-cell lymphoma and classical Hodgkinlymphoma.

“Tumor,” as used herein, refers to all neoplastic cell growth andproliferation, whether malignant or benign, and all pre-cancerous andcancerous cells and tissues. The terms “cancer”, “cancerous”, “cellproliferative disorder”, “proliferative disorder” and “tumor” are notmutually exclusive as referred to herein.

The term “tumor antigen,” as used herein, may be understood as thoseantigens that are presented on tumor cells. These antigens can bepresented on the cell surface with an extracellular part, which is oftencombined with a transmembrane and cytoplasmic part of the molecule.These antigens can sometimes be presented only by tumor cells and neverby the normal ones. Tumor antigens can be exclusively expressed on tumorcells or might represent a tumor specific mutation compared to normalcells. In this case, they are called tumor-specific antigens. Morecommon are tumor antigens that are presented by tumor cells and normalcells, and they are called tumor-associated antigens. Thesetumor-associated antigens can be overexpressed compared to normal cellsor are accessible for antibody binding in tumor cells due to the lesscompact structure of the tumor tissue compared to normal tissue. In oneaspect the tumor antigen is selected from those set forth in Table 1below.

“Effector functions” refer to those biological activities attributableto the Fc region of an antibody, which vary with the antibody isotype.Examples of antibody effector functions include: C1q binding andcomplement dependent cytotoxicity (CDC); Fc receptor binding;antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g. B cell receptor); and B cellactivation.

An “effective amount” of a compound, for example, an anti-CD3 antibodyof the invention or a composition (e.g., pharmaceutical composition)thereof, is at least the minimum amount required to achieve the desiredtherapeutic or prophylactic result, such as a measurable improvement orprevention of a particular disorder (e.g., a cell proliferativedisorder, e.g., cancer). An effective amount herein may vary accordingto factors such as the disease state, age, sex, and weight of thepatient, and the ability of the antibody to elicit a desired response inthe individual. An effective amount is also one in which any toxic ordetrimental effects of the treatment are outweighed by thetherapeutically beneficial effects. For prophylactic use, beneficial ordesired results include results such as eliminating or reducing therisk, lessening the severity, or delaying the onset of the disease,including biochemical, histological and/or behavioral symptoms of thedisease, its complications and intermediate pathological phenotypespresenting during development of the disease. For therapeutic use,beneficial or desired results include clinical results such asdecreasing one or more symptoms resulting from the disease, increasingthe quality of life of those suffering from the disease, decreasing thedose of other medications required to treat the disease, enhancingeffect of another medication such as via targeting, delaying theprogression of the disease, and/or prolonging survival. In the case ofcancer or tumor, an effective amount of the drug may have the effect inreducing the number of cancer cells; reducing the tumor size; inhibiting(i.e., slow to some extent or desirably stop) cancer cell infiltrationinto peripheral organs; inhibit (i.e., slow to some extent and desirablystop) tumor metastasis; inhibiting to some extent tumor growth; and/orrelieving to some extent one or more of the symptoms associated with thedisorder. An effective amount can be administered in one or moreadministrations. For purposes of this invention, an effective amount ofdrug, compound, or pharmaceutical composition is an amount sufficient toaccomplish prophylactic or therapeutic treatment either directly orindirectly. As is understood in the clinical context, an effectiveamount of a drug, compound, or pharmaceutical composition may or may notbe achieved in conjunction with another drug, compound, orpharmaceutical composition. Thus, an “effective amount” may beconsidered in the context of administering one or more therapeuticagents, and a single agent may be considered to be given in an effectiveamount if, in conjunction with one or more other agents, a desirableresult may be or is achieved.

The term “Fc region” herein is used to define a C-terminal region of animmunoglobulin heavy chain that contains at least a portion of theconstant region. The term includes native sequence Fc regions andvariant Fc regions. In one embodiment, a human IgG heavy chain Fc regionextends from Cys226, or from Pro230, to the carboxyl-terminus of theheavy chain. However, the C-terminal lysine (Lys447) of the Fc regionmay or may not be present. Unless otherwise specified herein, numberingof amino acid residues in the Fc region or constant region is accordingto the EU numbering system, also called the EU index, as described inKabat et al., Sequences of Proteins of Immunological Interest, 5th Ed.Public Health Service, National Institutes of Health, Bethesda, Md.,1991.

“Framework” or “FR” refers to variable domain residues other thanhypervariable region (HVR) residues. The FR of a variable domaingenerally consists of four FR domains: FR1, FR2, FR3, and FR4.Accordingly, the HVR and FR sequences generally appear in the followingsequence in VH (or VL): FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

The terms “full-length antibody,” “intact antibody,” and “wholeantibody” are used herein interchangeably to refer to an antibody havinga structure substantially similar to a native antibody structure orhaving heavy chains that contain an Fc region as defined herein.

A “growth inhibitory agent” when used herein refers to a compound orcomposition which inhibits growth of a cell either in vitro or in vivo.In one embodiment, growth inhibitory agent is growth inhibitory antibodythat prevents or reduces proliferation of a cell expressing an antigento which the antibody binds. In another embodiment, the growthinhibitory agent may be one which significantly reduces the percentageof cells in S phase. Examples of growth inhibitory agents include agentsthat block cell cycle progression (at a place other than S phase), suchas agents that induce G1 arrest and M-phase arrest. Classical M-phaseblockers include the vincas (vincristine and vinblastine), taxanes, andtopoisomerase II inhibitors such as doxorubicin, epirubicin,daunorubicin, etoposide, and bleomycin. Those agents that arrest G1 alsospill over into S-phase arrest, for example, DNA alkylating agents suchas tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin,methotrexate, 5-fluorouracil, and ara-C. Further information can befound in Mendelsohn and Israel, eds., The Molecular Basis of Cancer,Chapter 1, entitled “Cell cycle regulation, oncogenes, andantineoplastic drugs” by Murakami et al. (W.B. Saunders, Philadelphia,1995), e.g., p. 13. The taxanes (paclitaxel and docetaxel) areanticancer drugs both derived from the yew tree. Docetaxel (TAXOTERE®,Rhone-Poulenc Rorer), derived from the European yew, is a semisyntheticanalogue of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel anddocetaxel promote the assembly of microtubules from tubulin dimers andstabilize microtubules by preventing depolymerization, which results inthe inhibition of mitosis in cells.

The term “HER2-positive” cancer comprises cancer cells which have higherthan normal levels of HER2. Examples of HER2-positive cancer includeHER2-positive breast cancer and HER2-positive gastric cancer.Optionally, HER2-positive cancer has an immunohistochemistry (IHC) scoreof 2+ or 3+ and/or an in situ hybridization (ISH) amplificationratio≥2.0.

The terms “host cell,” “host cell line,” and “host cell culture” areused interchangeably and refer to cells into which exogenous nucleicacid has been introduced, including the progeny of such cells. Hostcells include “transformants” and “transformed cells,” which include theprimary transformed cell and progeny derived therefrom without regard tothe number of passages. Progeny may not be completely identical innucleic acid content to a parent cell, but may contain mutations. Mutantprogeny that have the same function or biological activity as screenedor selected for in the originally transformed cell are included herein.

A “human antibody” is one which possesses an amino acid sequence whichcorresponds to that of an antibody produced by a human or a human cellor derived from a non-human source that utilizes human antibodyrepertoires or other human antibody-encoding sequences. This definitionof a human antibody specifically excludes a humanized antibodycomprising non-human antigen-binding residues. Human antibodies can beproduced using various techniques known in the art, includingphage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381(1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available forthe preparation of human monoclonal antibodies are methods described inCole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See alsovan Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001).Human antibodies can be prepared by administering the antigen to atransgenic animal that has been modified to produce such antibodies inresponse to antigenic challenge, but whose endogenous loci have beendisabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181and 6,150,584 regarding XENOMOUSE™ technology). See also, for example,Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regardinghuman antibodies generated via a human B-cell hybridoma technology.

A “human consensus framework” is a framework which represents the mostcommonly occurring amino acid residues in a selection of humanimmunoglobulin VL or VH framework sequences. Generally, the selection ofhuman immunoglobulin VL or VH sequences is from a subgroup of variabledomain sequences. Generally, the subgroup of sequences is a subgroup asin Kabat et al., Sequences of Proteins of Immunological Interest, FifthEdition, NIH Publication 91-3242, Bethesda Md. (1991), vols. 1-3. In oneembodiment, for the VL, the subgroup is subgroup kappa I as in Kabat etal., supra. In one embodiment, for the VH, the subgroup is subgroup IIIas in Kabat et al., supra.

A “humanized” antibody refers to a chimeric antibody comprising aminoacid residues from non-human HVRs and amino acid residues from humanFRs. In certain embodiments, a humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the HVRs (e.g., CDRs) correspond tothose of a non-human antibody, and all or substantially all of the FRscorrespond to those of a human antibody. A humanized antibody optionallymay comprise at least a portion of an antibody constant region derivedfrom a human antibody. A “humanized form” of an antibody, e.g., anon-human antibody, refers to an antibody that has undergonehumanization.

The term “hypervariable region” or “HVR” as used herein refers to eachof the regions of an antibody variable domain which are hypervariable insequence (“complementarity determining regions” or “CDRs”) and/or formstructurally defined loops (“hypervariable loops”) and/or contain theantigen-contacting residues (“antigen contacts”). Generally, antibodiescomprise six HVRs: three in the VH (H1, H2, H3), and three in the VL(L1, L2, L3). Exemplary HVRs herein include:

(a) hypervariable loops occurring at amino acid residues 26-32 (L1),50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothiaand Lesk, J. Mol. Biol. 196:901-917 (1987));

(b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97(L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequencesof Proteins of Immunological Interest, 5th Ed. Public Health Service,National Institutes of Health, Bethesda, Md. (1991));

(c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55(L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum etal. J. Mol. Biol. 262: 732-745 (1996)); and

(d) combinations of (a), (b), and/or (c), including HVR amino acidresidues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1),26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).

Unless otherwise indicated, HVR residues and other residues in thevariable domain (e.g., FR residues) are numbered herein according toKabat et al., supra.

An “immunoconjugate” is an antibody conjugated to one or moreheterologous molecule(s), including but not limited to a cytotoxicagent.

A “subject” or an “individual” is a mammal. Mammals include, but are notlimited to, domesticated animals (e.g., cows, sheep, cats, dogs, andhorses), primates (e.g., humans and non-human primates such as monkeys),rabbits, and rodents (e.g., mice and rats). In certain embodiments, thesubject or individual is a human.

An “isolated” antibody is one which has been separated from a componentof its natural environment. In some embodiments, an antibody is purifiedto greater than 95% or 99% purity as determined by, for example,electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillaryelectrophoresis) or chromatographic (e.g., ion exchange or reverse phaseHPLC). For review of methods for assessment of antibody purity, see,e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

An “isolated” nucleic acid refers to a nucleic acid molecule that hasbeen separated from a component of its natural environment. An isolatednucleic acid includes a nucleic acid molecule contained in cells thatordinarily contain the nucleic acid molecule, but the nucleic acidmolecule is present extrachromosomally or at a chromosomal location thatis different from its natural chromosomal location.

“Isolated nucleic acid encoding an anti-CD3 antibody” refers to one ormore nucleic acid molecules encoding antibody heavy and light chains (orfragments thereof), including such nucleic acid molecule(s) in a singlevector or separate vectors, and such nucleic acid molecule(s) present atone or more locations in a host cell.

The term “monoclonal antibody” as used herein refers to an antibodyobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicaland/or bind the same epitope, except for possible variant antibodies,e.g., containing naturally occurring mutations or arising duringproduction of a monoclonal antibody preparation, such variants generallybeing present in minor amounts. In contrast to polyclonal antibodypreparations, which typically include different antibodies directedagainst different determinants (epitopes), each monoclonal antibody of amonoclonal antibody preparation is directed against a single determinanton an antigen. Thus, the modifier “monoclonal” indicates the characterof the antibody as being obtained from a substantially homogeneouspopulation of antibodies, and is not to be construed as requiringproduction of the antibody by any particular method. For example, themonoclonal antibodies to be used in accordance with the presentinvention may be made by a variety of techniques, including but notlimited to the hybridoma method, recombinant DNA methods, phage-displaymethods, and methods utilizing transgenic animals containing all or partof the human immunoglobulin loci, such methods and other exemplarymethods for making monoclonal antibodies being described herein.

A “naked antibody” refers to an antibody that is not conjugated to aheterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The nakedantibody may be present in a pharmaceutical formulation.

“Native antibodies” refer to naturally occurring immunoglobulinmolecules with varying structures. For example, native IgG antibodiesare heterotetrameric glycoproteins of about 150,000 daltons, composed oftwo identical light chains and two identical heavy chains that aredisulfide-bonded. From N- to C-terminus, each heavy chain has a variableregion (VH), also called a variable heavy domain or a heavy chainvariable domain, followed by three constant domains (CH1, CH2, and CH3).Similarly, from N- to C-terminus, each light chain has a variable region(VL), also called a variable light domain or a light chain variabledomain, followed by a constant light (CL) domain. The light chain of anantibody may be assigned to one of two types, called kappa (κ) andlambda (A), based on the amino acid sequence of its constant domain.

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,combination therapy, contraindications and/or warnings concerning theuse of such therapeutic products.

The term “PD-1 axis binding antagonist” refers to a molecule thatinhibits the interaction of a PD-1 axis binding partner with either oneor more of its binding partner, so as to remove T-cell dysfunctionresulting from signaling on the PD-1 signaling axis—with a result beingto restore or enhance T-cell function (e.g., proliferation, cytokineproduction, target cell killing). As used herein, a PD-1 axis bindingantagonist includes a PD-1 binding antagonist, a PD-L1 bindingantagonist and a PD-L2 binding antagonist.

The term “PD-1 binding antagonist” refers to a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PD-1 with one or more of its bindingpartners, such as PD-L1, PD-L2. In some embodiments, the PD-1 bindingantagonist is a molecule that inhibits the binding of PD-1 to one ormore of its binding partners. In a specific aspect, the PD-1 bindingantagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. Forexample, PD-1 binding antagonists include anti-PD-1 antibodies, antigenbinding fragments thereof, immunoadhesins, fusion proteins,oligopeptides and other molecules that decrease, block, inhibit,abrogate or interfere with signal transduction resulting from theinteraction of PD-1 with PD-L1 and/or PD-L2. In one embodiment, a PD-1binding antagonist reduces the negative co-stimulatory signal mediatedby or through cell surface proteins expressed on T lymphocytes mediatedsignaling through PD-1 so as render a dysfunctional T-cell lessdysfunctional (e.g., enhancing effector responses to antigenrecognition). In some embodiments, the PD-1 binding antagonist is ananti-PD-1 antibody. In a specific aspect, a PD-1 binding antagonist isMDX-1106 (nivolumab) described herein. In another specific aspect, aPD-1 binding antagonist is MK-3475 (lambrolizumab) described herein. Inanother specific aspect, a PD-1 binding antagonist is CT-011(pidilizumab) described herein. In another specific aspect, a PD-1binding antagonist is AMP-224 described herein.

The term “PD-L1 binding antagonist” refers to a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PD-L1 with either one or more of itsbinding partners, such as PD-1, B7-1. In some embodiments, a PD-L1binding antagonist is a molecule that inhibits the binding of PD-L1 toits binding partners. In a specific aspect, the PD-L1 binding antagonistinhibits binding of PD-L1 to PD-1 and/or B7-1. In some embodiments, thePD-L1 binding antagonists include anti-PD-L1 antibodies, antigen bindingfragments thereof, immunoadhesins, fusion proteins, oligopeptides andother molecules that decrease, block, inhibit, abrogate or interferewith signal transduction resulting from the interaction of PD-L1 withone or more of its binding partners, such as PD-1, B7-1. In oneembodiment, a PD-L1 binding antagonist reduces the negativeco-stimulatory signal mediated by or through cell surface proteinsexpressed on T lymphocytes mediated signaling through PD-L1 so as torender a dysfunctional T-cell less dysfunctional (e.g., enhancingeffector responses to antigen recognition). In some embodiments, a PD-L1binding antagonist is an anti-PD-L1 antibody. In a specific aspect, ananti-PD-L1 antibody is YW243.55.S70 described herein. In anotherspecific aspect, an anti-PD-L1 antibody is MDX-1105 described herein. Instill another specific aspect, an anti-PD-L1 antibody is MPDL3280Adescribed herein. In still another specific aspect, an anti-PD-L1antibody is MED14736 described herein.

The term “PD-L2 binding antagonist” refers to a molecule that decreases,blocks, inhibits, abrogates or interferes with signal transductionresulting from the interaction of PD-L2 with either one or more of itsbinding partners, such as PD-1. In some embodiments, a PD-L2 bindingantagonist is a molecule that inhibits the binding of PD-L2 to one ormore of its binding partners. In a specific aspect, the PD-L2 bindingantagonist inhibits binding of PD-L2 to PD-1. In some embodiments, thePD-L2 antagonists include anti-PD-L2 antibodies, antigen bindingfragments thereof, immunoadhesins, fusion proteins, oligopeptides andother molecules that decrease, block, inhibit, abrogate or interferewith signal transduction resulting from the interaction of PD-L2 witheither one or more of its binding partners, such as PD-1. In oneembodiment, a PD-L2 binding antagonist reduces the negativeco-stimulatory signal mediated by or through cell surface proteinsexpressed on T lymphocytes mediated signaling through PD-L2 so as rendera dysfunctional T-cell less dysfunctional (e.g., enhancing effectorresponses to antigen recognition). In some embodiments, a PD-L2 bindingantagonist is an immunoadhesin.

The term “protein,” as used herein, refers to any native protein fromany vertebrate source, including mammals such as primates (e.g. humans)and rodents (e.g., mice and rats), unless otherwise indicated. The termencompasses “full-length,” unprocessed protein as well as any form ofthe protein that results from processing in the cell. The term alsoencompasses naturally occurring variants of the protein, e.g., splicevariants or allelic variants. Proteins according to the inventioninclude, for example, any protein listed in Table 1.

“Percent (%) amino acid sequence identity” with respect to a referencepolypeptide sequence is defined as the percentage of amino acid residuesin a candidate sequence that are identical with the amino acid residuesin the reference polypeptide sequence, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent sequenceidentity, and not considering any conservative substitutions as part ofthe sequence identity. Alignment for purposes of determining percentamino acid sequence identity can be achieved in various ways that arewithin the skill in the art, for instance, using publicly availablecomputer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR)software. Those skilled in the art can determine appropriate parametersfor aligning sequences, including any algorithms needed to achievemaximal alignment over the full length of the sequences being compared.For purposes herein, however, % amino acid sequence identity values aregenerated using the sequence comparison computer program ALIGN-2. TheALIGN-2 sequence comparison computer program was authored by Genentech,Inc., and the source code has been filed with user documentation in theU.S. Copyright Office, Washington D.C., 20559, where it is registeredunder U.S. Copyright Registration No. TXU510087. The ALIGN-2 program ispublicly available from Genentech, Inc., South San Francisco, Calif., ormay be compiled from the source code. The ALIGN-2 program should becompiled for use on a UNIX operating system, including digital UNIXV4.0D. All sequence comparison parameters are set by the ALIGN-2 programand do not vary.

In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:100 times the fraction X/Ywhere X is the number of amino acid residues scored as identical matchesby the sequence alignment program ALIGN-2 in that program's alignment ofA and B, and where Y is the total number of amino acid residues in B. Itwill be appreciated that where the length of amino acid sequence A isnot equal to the length of amino acid sequence B, the % amino acidsequence identity of A to B will not equal the % amino acid sequenceidentity of B to A. Unless specifically stated otherwise, all % aminoacid sequence identity values used herein are obtained as described inthe immediately preceding paragraph using the ALIGN-2 computer program.

The term “pharmaceutical formulation” refers to a preparation which isin such form as to permit the biological activity of an activeingredient contained therein to be effective, and which contains noadditional components which are unacceptably toxic to a subject to whichthe formulation would be administered.

A “pharmaceutically acceptable carrier” refers to an ingredient in apharmaceutical formulation, other than an active ingredient, which isnontoxic to a subject. A pharmaceutically acceptable carrier includes,but is not limited to, a buffer, excipient, stabilizer, or preservative.

As used herein, “treatment” (and grammatical variations thereof such as“treat” or “treating”) refers to clinical intervention in an attempt toalter the natural course of the individual being treated, and can beperformed either for prophylaxis or during the course of clinicalpathology. Desirable effects of treatment include, but are not limitedto, preventing occurrence or recurrence of disease, alleviation ofsymptoms, diminishment of any direct or indirect pathologicalconsequences of the disease, preventing metastasis, decreasing the rateof disease progression, amelioration or palliation of the disease state,and remission or improved prognosis. In some embodiments, antibodies ofthe invention are used to delay development of a disease or to slow theprogression of a disease.

As used herein, “delaying progression” of a disorder or disease means todefer, hinder, slow, retard, stabilize, and/or postpone development ofthe disease or disorder (e.g., a cell proliferative disorder, e.g.,cancer). This delay can be of varying lengths of time, depending on thehistory of the disease and/or individual being treated. As is evident toone skilled in the art, a sufficient or significant delay can, ineffect, encompass prevention, in that the individual does not developthe disease. For example, a late stage cancer, such as development ofmetastasis, may be delayed.

By “reduce” or “inhibit” is meant the ability to cause an overalldecrease, for example, of 20% or greater, of 50% or greater, or of 75%,85%, 90%, 95%, or greater. In certain embodiments, reduce or inhibit canrefer to the effector function of an antibody that is mediated by theantibody Fc region, such effector functions specifically includingcomplement-dependent cytotoxicity (CDC), antibody-dependent cellularcytotoxicity (ADCC), and antibody-dependent cellular phagocytosis(ADCP).

The term “variable region” or “variable domain” refers to the domain ofan antibody heavy or light chain that is involved in binding theantibody to antigen. The variable domains of the heavy chain and lightchain (VH and VL, respectively) of a native antibody generally havesimilar structures, with each domain comprising four conserved frameworkregions (FRs) and three hypervariable regions (HVRs). (See, e.g., Kindtet al. Kuby Immunology, 6^(th) ed., W.H. Freeman and Co., page 91(2007).) A single VH or VL domain may be sufficient to conferantigen-binding specificity. Furthermore, antibodies that bind aparticular antigen may be isolated using a VH or VL domain from anantibody that binds the antigen to screen a library of complementary VLor VH domains, respectively. See, e.g., Portolano et al., J. Immunol.150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

The term “vector,” as used herein, refers to a nucleic acid moleculecapable of propagating another nucleic acid to which it is linked. Theterm includes the vector as a self-replicating nucleic acid structure aswell as the vector incorporated into the genome of a host cell intowhich it has been introduced. Certain vectors are capable of directingthe expression of nucleic acids to which they are operatively linked.Such vectors are referred to herein as “expression vectors.”

As used herein, “administering” is meant a method of giving a dosage ofa compound (e.g., an anti-CD3 antibody of the invention or a nucleicacid encoding an anti-CD3 antibody of the invention) or a composition(e.g., a pharmaceutical composition, e.g., a pharmaceutical compositionincluding an anti-CD3 antibody of the invention) to a subject. Thecompositions utilized in the methods described herein can beadministered, for example, intramuscularly, intravenously,intradermally, percutaneously, intraarterially, intraperitoneally,intralesionally, intracranially, intraarticularly, intraprostatically,intrapleurally, intratracheally, intranasally, intravitreally,intravaginally, intrarectally, topically, intratumorally, peritoneally,subcutaneously, subconjunctivally, intravesicularlly, mucosally,intrapericardially, intraumbilically, intraocularly, orally, topically,locally, by inhalation, by injection, by infusion, by continuousinfusion, by localized perfusion bathing target cells directly, bycatheter, by lavage, in cremes, or in lipid compositions. The method ofadministration can vary depending on various factors (e.g., the compoundor composition being administered and the severity of the condition,disease, or disorder being treated).

II. Compositions and Methods

In one aspect, the invention is based, in part, on anti-CD3 antibodies.In certain embodiments, the anti-CD3 antibodies are multispecific (e.g.,bispecific) and bind, in addition to CD3 or a fragment thereof, a secondbiological molecule (e.g., a cell surface antigen, e.g., a tumorantigen). Antibodies of the invention are useful, for example, fortreating or delaying the progression of a cell proliferative disorder(e.g., cancer) or an autoimmune disorder, or for enhancing immunefunction in a subject having such a disorder.

A. Exemplary Anti-CD3 Antibodies

In one aspect, the invention provides isolated antibodies that bind toCD3 (e.g., CD3ε and/or CD3γ).

For example, in one aspect, the invention provides an anti-CD3 antibodyhaving a binding domain comprising at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ IDNO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 301-304,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 305-308, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain includingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 184 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 185.In other instances, the anti-CD3 antibody comprises at least one (e.g.,1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, andFR-H4 comprising the sequences of SEQ ID NOs: 293-296, respectively,and/or at least one (e.g., 1, 2, 3, or 4) of the light chain frameworkregions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQID NOs: 297-300, respectively. In some instances, the anti-CD3 antibodymay have a VH domain comprising an amino acid sequence having at leastat least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 186 and/or a VL domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 187. In a particular instance, the anti-CD3 antibody can be 40G5c,or a derivative or clonal relative thereof.

In another aspect, an antibody of the invention comprises (a) a VHdomain comprising at least one, at least two, or all three VH HVRsequences selected from (i) HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 1, (ii) HVR-H2 comprising the amino acid sequence of SEQ IDNO: 2, and (iii) HVR-H3 comprising an amino acid sequence selected fromSEQ ID NO: 3; and (b) a VL domain comprising at least one, at least two,or all three VL HVR sequences selected from (i) HVR-L1 comprising theamino acid sequence of SEQ ID NO: 4, (ii) HVR-L2 comprising the aminoacid sequence of SEQ ID NO: 5, and (iii) HVR-L3 comprising the aminoacid sequence of SEQ ID NO: 6. In some instances, the anti-CD3 antibodymay have a VH domain comprising the amino acid sequence of SEQ ID NO:184 and a VL domain comprising the amino acid sequence of SEQ ID NO:185. In some instances, the anti-CD3 antibody may have a VH domaincomprising the amino acid sequence of SEQ ID NO: 186 and a VL domaincomprising the amino acid sequence of SEQ ID NO: 187. In a particularinstance, the anti-CD3 antibody can be 40G5c, or a derivative or clonalrelative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 181; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 182.

In certain embodiments, any one or more amino acids of an anti-CD3antibody as provided above are substituted at the following HVRpositions:

-   -   in HVR-H3 (SEQ ID NO: 181): positions 1, 2, 5, 6, and 7; and    -   in HVR-L3 (SEQ ID NO: 182): positions 1, 2, 4, and 5 In certain        embodiments, the substitutions are conservative substitutions,        as provided herein. In certain embodiments, any one or more of        the following substitutions may be made in any combination:    -   in HVR-H3 (SEQ ID NO: 181): D1T or S; S1D or T; T1D or S; G2A or        S; A2G or S; S2A or G; R5N; N5R; Y6A; A6Y; A7Y; and Y7A; and    -   in HVR-L3 (SEQ ID NO: 182): K1T; T1K; Q2A; A2Q; F4A; A4F; 15A        and A51.

For example, in some instances, the invention provides an anti-CD3antibody having a binding domain comprising at least one, two, three,four, five, or six HVRs selected from (a) HVR-H1 comprising the aminoacid sequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequenceof SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ IDNO: 10; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12. Insome instances, the anti-CD3 antibody may have a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 188 and/or a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 189. In a particular instance, theanti-CD3 antibody can be 38E4v1, or a derivative or clonal relativethereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 13; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 12. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 190 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 191. In a particular instance, the anti-CD3antibody can be 38E4v2, or a derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 14. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 192 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 193. In a particular instance, the anti-CD3antibody can be 38E4v3, or a derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 15. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 194 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 195. In a particular instance, the anti-CD3antibody can be 38E4v4, or a derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 16. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 196 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 197. In a particular instance, the anti-CD3antibody can be 38E4v5, or a derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 12. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 198 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 199. In a particular instance, the anti-CD3antibody can be 38E4v6, or a derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 18; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 12. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 200 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 201. In a particular instance, the anti-CD3antibody can be 38E4v7, or a derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 19; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 12. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 202 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 203. In a particular instance, the anti-CD3antibody can be 38E4v8, or a derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 20; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 12. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 204 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 205. In a particular instance, the anti-CD3antibody can be 38E4v9, or a derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 7; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8;(c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 21; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 11; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 22. In some instances,the anti-CD3 antibody may have a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 206 and/or a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 207. In a particular instance, the anti-CD3antibody can be 38E4c, or a derivative or clonal relative thereof.

In some instances, any one of the 38E4v1-38E4v9 and 38E4c anti-CD3antibodies may comprise at least one (e.g., 1, 2, 3, or 4) of heavychain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising thesequences of SEQ ID NOs: 309-312, respectively, and/or at least one(e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2,FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 313-316,respectively.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:183; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 28.

In certain embodiments, any one or more amino acids of an anti-CD3antibody as provided above are substituted at the following HVRpositions:

-   -   in HVR-H2 (SEQ ID NO: 183): positions 9, 12, 13, 14, 15, and 17.

In certain embodiments, the substitutions are conservativesubstitutions, as provided herein. In certain embodiments, any one ormore of the following substitutions may be made in any combination:

-   -   in HVR-H2 (SEQ ID NO: 183): S9T; T9S; N12A; A12N; Q13D; D13Q;        K14S; S14K; F15V; V15F; D17G; and G17D.

For example, in some instances, the invention provides an anti-CD3antibody having a binding domain comprising at least one, two, three,four, five, or six HVRs selected from (a) HVR-H1 comprising the aminoacid sequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequenceof SEQ ID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQID NO: 26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO:27; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28.In some instances, the anti-CD3 antibody comprises at least one (e.g.,1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, andFR-H4 comprising the sequences of SEQ ID NOs: 317-320, respectively,and/or at least one (e.g., 1, 2, 3, or 4) of the light chain frameworkregions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQID NOs: 321-324, respectively. In some instances, the anti-CD3 antibodymay have a VH domain comprising an amino acid sequence having at least90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 208and/or a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 209.In a particular instance, the anti-CD3 antibody can be UCHT1v9, or aderivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:29; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 28. In some instances,the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) ofheavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprisingthe sequences of SEQ ID NOs: 325-328, respectively, and/or at least one(e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2,FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 329-332,respectively. In some instances, the anti-CD3 antibody may have a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 210 and/or a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 211. In aparticular instance, the anti-CD3 antibody can be UCHT1v1, or aderivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 23; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:30; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 25; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 26; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 27; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 28. In some instances,the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) ofheavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprisingthe sequences of SEQ ID NOs: 333-336, respectively, and/or at least one(e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2,FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 337-340,respectively. In some instances, the anti-CD3 antibody may have a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 212 and/or a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 213. In aparticular instance, the anti-CD3 antibody can be UCHT1vM1, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 31; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 32; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 33; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 34; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 35; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 36. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 341-344,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 345-348, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 214 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 215.In other instances, the anti-CD3 antibody comprises at least one (e.g.,1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, andFR-H4 comprising the sequences of SEQ ID NOs: 349-352, respectively,and/or at least one (e.g., 1, 2, 3, or 4) of the light chain frameworkregions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQID NOs: 353-356, respectively. In some instances, the anti-CD3 antibodymay have a VH domain comprising an amino acid sequence having at leastat least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 216 and/or a VL domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 217. In a particular instance, the anti-CD3 antibody can be SP34v52,or a derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 37; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 38; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 39; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 40; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 41; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 42. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 357-360,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 361-364, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 218 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 219.In other instances, the anti-CD3 antibody comprises at least one (e.g.,1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, andFR-H4 comprising the sequences of SEQ ID NOs: 365-368, respectively,and/or at least one (e.g., 1, 2, 3, or 4) of the light chain frameworkregions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQID NOs: 369-372, respectively. In some instances, the anti-CD3 antibodymay have a VH domain comprising an amino acid sequence having at leastat least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 220 and/or a VL domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 221. In a particular instance, the anti-CD3 antibody can be 41 D9a,or a derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 43; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 44; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 45; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 46; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 47; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 48. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 373-376,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 377-380, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 222 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 223.In other instances, the anti-CD3 antibody comprises at least one (e.g.,1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, andFR-H4 comprising the sequences of SEQ ID NOs: 381-384, respectively,and/or at least one (e.g., 1, 2, 3, or 4) of the light chain frameworkregions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQID NOs: 385-388, respectively. In some instances, the anti-CD3 antibodymay have a VH domain comprising an amino acid sequence having at leastat least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 226 and/or a VL domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 227. In a particular instance, the anti-CD3 antibody can be 13A3, ora derivative or clonal relative thereof.

In some instances, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixHVRs selected from (a) HVR-H1 comprising the amino acid sequence of SEQID NO: 43; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:44; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 45; (d)HVR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 47; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 48. In some instances,the anti-CD3 antibody comprises at least one (e.g., 1, 2, 3, or 4) ofheavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprisingthe sequences of SEQ ID NOs: 389-392, respectively, and/or at least one(e.g., 1, 2, 3, or 4) of the light chain framework regions FR-L1, FR-L2,FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 393-396,respectively. In some instances, the anti-CD3 antibody may have a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 224 and/or a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 225. In aparticular instance, the anti-CD3 antibody can be 13A3.v2, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 49; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 50; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 51; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 52; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 53; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 54. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 397-400,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 401-404, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 228 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 229.In other instances, the anti-CD3 antibody comprises at least one (e.g.,1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, andFR-H4 comprising the sequences of SEQ ID NOs: 405-408, respectively,and/or at least one (e.g., 1, 2, 3, or 4) of the light chain frameworkregions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQID NOs: 409-412, respectively. In some instances, the anti-CD3 antibodymay have a VH domain comprising an amino acid sequence having at leastat least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 230 and/or a VL domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 231. In a particular instance, the anti-CD3 antibody can be 30A1, ora derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 55; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 56; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 57; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 58; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 59; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 60. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 413-416,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 417-420, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 232 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 233.In a particular instance, the anti-CD3 antibody can be 30A1.v2, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 61; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 62; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 63; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 64; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 65; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 66. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 421-424,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 425-428, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 234 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 235.In a particular instance, the anti-CD3 antibody can be h21A9, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 67; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 68; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 69; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 70; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 71; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 72. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 429-432,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 433-436, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 236 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 237.In a particular instance, the anti-CD3 antibody can be 21B2, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 73; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 74; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 75; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 76; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 77; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 78. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 437-440,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 441-444, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 238 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 239.In a particular instance, the anti-CD3 antibody can be 125A1, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 79; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 80; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 81; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 82; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 83; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 84. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 445-448,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 449-452, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 240 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 241.In a particular instance, the anti-CD3 antibody can be 72H6, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 85; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 86; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 87; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 88; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 89; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 90. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 453-456,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 457-460, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 242 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 243.In a particular instance, the anti-CD3 antibody can be 19B1, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 91; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 92; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 93; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 94; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 95; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 96. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 461-464,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 465-468, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 244 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 245.In a particular instance, the anti-CD3 antibody can be 71H7, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 97; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 98; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 99; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 100; (e) HVR-L2 comprising the amino acid sequence of SEQID NO: 101; and (f) HVR-L3 comprising the amino acid sequence of SEQ IDNO: 102. In some instances, the anti-CD3 antibody comprises at least one(e.g., 1, 2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2,FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 469-472,respectively, and/or at least one (e.g., 1, 2, 3, or 4) of the lightchain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising thesequences of SEQ ID NOs: 473-476, respectively. In some instances, theanti-CD3 antibody may have a heavy chain variable (VH) domain comprisingan amino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 246 and/or a light chain variable(VL) domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 247.In a particular instance, the anti-CD3 antibody can be 14C7, or aderivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 103; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 477-480, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 481-484, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 248 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 249. In a particular instance, the anti-CD3 antibody can be 127B3,or a derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 109; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 485-488, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 489-492, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 250 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 251. In a particular instance, the anti-CD3 antibody can be 18F12,or a derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 115; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 493-496, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 497-500, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 252 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 253. In a particular instance, the anti-CD3 antibody can be 27H5-1,or a derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 121; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 501-504, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 505-508, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 254 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 255. In a particular instance, the anti-CD3 antibody can be 39B7, ora derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 127; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 509-512, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 513-516, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 256 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 257. In a particular instance, the anti-CD3 antibody can be 40D2, ora derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 517-520, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 521-524, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 258 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 259. In a particular instance, the anti-CD3 antibody can be 79B7, ora derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 525-528, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 529-532, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 260 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 261. In a particular instance, the anti-CD3 antibody can be 95A2, ora derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 533-536, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 537-540, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 262 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 263. In a particular instance, the anti-CD3 antibody can be 118G9,or a derivative or clonal relative thereof.

In one aspect, the invention provides an anti-CD3 antibody having abinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156. In some instances, the anti-CD3 antibodycomprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 541-544, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 545-548, respectively. In someinstances, the anti-CD3 antibody may have a heavy chain variable (VH)domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 264 and/or a lightchain variable (VL) domain comprising an amino acid sequence having atleast 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity) to, or the sequence of, SEQ IDNO: 265. In a particular instance, the anti-CD3 antibody can be Rab17,or a derivative or clonal relative thereof.

In any of the above embodiments, an anti-CD3 antibody is humanized. Inone embodiment, an anti-CD3 antibody comprises HVRs as in any of theabove embodiments, and further comprises an acceptor human framework,e.g., a human immunoglobulin framework or a human consensus framework.

In another aspect, an anti-CD3 antibody is provided, wherein theantibody comprises a VH as in any of the embodiments provided above, anda VL as in any of the embodiments provided above, wherein one or both ofthe variable domain sequences include post-translational modifications.

In a further aspect, the invention provides an antibody that binds tothe same epitope as an anti-CD3 antibody provided herein. For example,in certain embodiments, an antibody is provided that binds to the sameepitope as an anti-CD3 antibody comprising a VH sequence of SEQ ID NO:184 and a VL sequence of SEQ ID NO: 185. In certain embodiments, anantibody is provided that binds to an epitope within a fragment of CD3(e.g., human CD3ε) consisting of amino acids 1-26 (SEQ ID NO: 283) or1-27 (SEQ ID NO: 278) of human CD3ε.

In another aspect, the invention provides an antibody that binds aunique CD3 epitope. In certain embodiments, the anti-CD3 antibody of theinvention makes unique contacts with amino acids of human CD3ε at adistance of 3.5 Angstroms, 3.25 Angstroms, 3.00 Angstroms, 2.75Angstroms, or less. In certain embodiments, an antibody is provided thatbinds to an epitope consisting of one, two, three, four, or five aminoacids of human CD3ε at a distance of 3.5 Angstroms, 3.25 Angstroms, 3.00Angstroms, 2.75 Angstroms or less. In one embodiment, the anti-CD3antibody of the invention makes unique contacts with amino acids ofhuman CD3ε at a distance of 3.5 Angstroms or less. In certainembodiments, an antibody is provided that binds to an epitope consistingof one, two, three, four, or five amino acids of human CD3ε at adistance of 3.5 Angstroms or less. For example, in certain embodiments,an antibody is provided that binds to an epitope consisting of aminoacids of human CD3ε selected from Gln1, Asp2, Asn4, Glu6, and Met7. Inone particular embodiment, the anti-CD3 antibody binds to an epitopethat specifically includes Glu6. In certain other embodiments, anantibody is provided that does not bind to an epitope that includeshuman CD3ε amino acid Glu5. In certain other embodiments, an antibody isprovided that does not bind to an epitope that includes human CD3ε aminoacids Gly3 and Glu5.

An anti-CD3 epitope may be determined by anti-CD3 antibody binding topeptide fragments of the epitope. Alternatively, an anti-CD3 epitope maybe determined by alanine scanning mutagenesis. In one embodiment, areduction in binding of an anti-CD3 antibody to mutated CD3 by 20%, 30%,50%, 80% or more indicates the amino acid residue of CD3 mutated in analanine scanning mutagenesis assay is an epitope residue for thatanti-CD3 antibody. Alternatively, an anti-CD3 epitope may be determinedby mass spectrometry. In some embodiments, the epitope is determined bycrystallography (e.g., crystallography methods described in theExamples).

In some embodiments, the epitope as determined by crystallography isdetermined using amino acids Q1-M7 of CD3. In some embodiments, theepitope as determined by crystallography is determined using amino acidsQDGNEEMGGITQTPYK (SEQ ID NO: 284) of CD3.

In some embodiments, the epitope as determined by crystallography may beperformed by combining the anti-CD3 antibody Fab, dissolved in 0.15 MNaCl, 25 mM tris, pH 7.5 at 10 mg/ml, with a 2-fold molar excess (1 mg)of CD3ε peptide and initially screening a sparse matrix of precipitantsin a sitting drop vapor diffusion format. Optimized crystals may begrown from a 1:1 mixture with reservoir solution containing 70% v/vmethyl-pentanediol, and 0.1 M HEPES buffer at pH 7.5. The reservoir maybe used as a cryoprotectant. The crystals may be transferred tocryogenic temperature by sudden immersion into liquid nitrogen.

The diffraction data for crystals may be collected at Advanced PhotonSource beam line 221D, using a MAR300 CCD detector. The recordeddiffractions may be integrated and scaled using the program HKL2000.

The structure may be phased by molecular replacement (MR) method usingprogram Phaser. For example, the MR search model is a Fab subunitderived from a crystal structure of HGFA/Fab complex (PDB code: 2R0L).The CD3ε peptide is built into the structure based on a Fo-Fc map. Thestructure may be subsequently refined with programs REFMAC5 and PHENIXusing the maximum likelihood target functions, anisotropic individualB-factor refinement method, and TLS refinement method, to achieveconvergence.

In certain other embodiments, an antibody is provided that includes aparatope that binds to the same epitope as an anti-CD3 antibody providedherein. For example, in certain embodiments an antibody is provided thatbinds to the same epitope as an anti-CD3 antibody paratope comprisingamino acids that form contacts at a distance of 3.5 Angstroms or less.In certain embodiments, an antibody is provided that binds to the sameepitope as an anti-CD3 antibody paratope consisting of amino acids ofthe VH region of an anti-CD3 antibody selected from the group comprising33Tyr, 35His, 50Trp, 97Tyr, and 98Ser. In certain embodiments, anantibody is provided that binds to the same epitope as an anti-CD3antibody paratope consisting of one, two, three, four, or five aminoacids of the VH region of an anti-CD3 antibody selected from the groupcomprising 33Tyr, 35His, 50Trp, 97Tyr, and 98Ser. In certainembodiments, an antibody is provided that binds to the same epitope asan anti-CD3 antibody paratope consisting of amino acids of the VL regionof an anti-CD3 antibody selected from the group comprising 27Arg, 27Asn,30Lys, 32Tyr, 92Phe, 94Leu, and 96Arg. In certain embodiments, anantibody is provided that binds to the same epitope as an anti-CD3antibody paratope consisting of one, two, three, four, five, six, orseven amino acids of the VL region of an anti-CD3 antibody selected fromthe group comprising 27Arg, 27Asn, 30Lys, 32Tyr, 92Phe, 94Leu, and96Arg. In an optional embodiment, an antibody is provided that does notbind to the same epitope as an anti-CD3 antibody paratope consisting ofamino acids of the VL region comprising 91Ser. In a further aspect ofthe invention, an anti-CD3 antibody according to any of the aboveembodiments is a monoclonal antibody, comprising a chimeric, humanized,or human antibody. In one embodiment, an anti-CD3 antibody is anantibody fragment, for example, a Fv, Fab, Fab′, scFv, diabody, orF(ab′)₂ fragment. In another embodiment, the antibody is a full lengthantibody, e.g., an intact IgG antibody (e.g., an intact IgG1 antibody)or other antibody class or isotype as defined herein.

In a further aspect, an anti-CD3 antibody according to any of the aboveembodiments may incorporate any of the features, singly or incombination, as described in Sections 1-7 below.

1. Antibody Affinity

In certain embodiments, an antibody provided herein has a dissociationconstant (Kd) of ≤1 μM, ≤100 nM, ≤10 nM, ≤1 nM, ≤0.1 nM, ≤0.01 nM, or≤0.001 nM (e.g., 10⁻⁸ M or less, e.g., from 10⁻⁸ M to 10⁻¹³ M, e.g.,from 10⁻⁹ M to 10⁻¹³ M).

In one embodiment, Kd is measured by a radiolabeled antigen bindingassay (RIA). In one embodiment, an RIA is performed with the Fab versionof an antibody of interest and its antigen. For example, solutionbinding affinity of Fabs for antigen is measured by equilibrating Fabwith a minimal concentration of (¹²⁵I)-labeled antigen in the presenceof a titration series of unlabeled antigen, then capturing bound antigenwith an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol.Biol. 293:865-881 (1999)). To establish conditions for the assay,MICROTITER® multi-well plates (Thermo Scientific) are coated overnightwith 5 μg/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mMsodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovineserum albumin in PBS for two to five hours at room temperature(approximately 23° C.). In a non-adsorbent plate (Nunc #269620), 100 pMor 26 pM [¹²⁵I]-antigen are mixed with serial dilutions of a Fab ofinterest (e.g., consistent with assessment of the anti-VEGF antibody,Fab-12, in Presta et al., Cancer Res. 57:4593-4599 (1997)). The Fab ofinterest is then incubated overnight; however, the incubation maycontinue for a longer period (e.g., about 65 hours) to ensure thatequilibrium is reached. Thereafter, the mixtures are transferred to thecapture plate for incubation at room temperature (e.g., for one hour).The solution is then removed and the plate washed eight times with 0.1%polysorbate 20 (TWEEN-20®) in PBS. When the plates have dried, 150μl/well of scintillant (MICROSCINT-20™; Packard) is added, and theplates are counted on a TOPCOUNT™ gamma counter (Packard) for tenminutes. Concentrations of each Fab that give less than or equal to 20%of maximal binding are chosen for use in competitive binding assays.

According to another embodiment, Kd is measured using a BIACORE® surfaceplasmon resonance assay. For example, an assay using a BIACORE®-2000 ora BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) is performed at 25° C.with immobilized antigen CM5 chips at ˜10 response units (RU). In oneembodiment, carboxymethylated dextran biosensor chips (CM5, BIACORE,Inc.) are activated with N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to thesupplier's instructions. Antigen is diluted with 10 mM sodium acetate,pH 4.8, to 5 μg/ml (˜0.2 μM) before injection at a flow rate of 5μl/minute to achieve approximately 10 response units (RU) of coupledprotein. Following the injection of antigen, 1 M ethanolamine isinjected to block unreacted groups. For kinetics measurements, two-foldserial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25° C. at a flowrate of approximately 25 μl/min. Association rates (k_(on)) anddissociation rates (k_(off)) are calculated using a simple one-to-oneLangmuir binding model (BIACORE® Evaluation Software version 3.2) bysimultaneously fitting the association and dissociation sensorgrams. Theequilibrium dissociation constant (Kd) is calculated as the ratiok_(on)/k_(off). See, for example, Chen et al., J. Mol. Biol. 293:865-881(1999). If the on-rate exceeds 10⁶M⁻¹ s⁻¹ by the surface plasmonresonance assay above, then the on-rate can be determined by using afluorescent quenching technique that measures the increase or decreasein fluorescence emission intensity (excitation=295 nm; emission=340 nm,16 nm band-pass) at 25° C. of a 20 nM anti-antigen antibody (Fab form)in PBS, pH 7.2, in the presence of increasing concentrations of antigenas measured in a spectrometer, such as a stop-flow equippedspectrophometer (Aviv Instruments) or a 8000-series SLM-AMINCO™spectrophotometer (ThermoSpectronic) with a stirred cuvette.

2. Antibody Fragments

In certain embodiments, an antibody provided herein is an antibodyfragment. Antibody fragments include, but are not limited to, Fab, Fab′,Fab′-SH, F(ab′)₂, Fv, and scFv fragments, and other fragments describedbelow. For a review of certain antibody fragments, see Hudson et al.Nat. Med. 9:129-134 (2003). For a review of scFv fragments, see, e.g.,Pluckthün, in The Pharmacology of Monoclonal Antibodies, vol. 113,Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315(1994); see also WO 93/16185; and U.S. Pat. Nos. 5,571,894 and5,587,458. For discussion of Fab and F(ab′)₂ fragments comprisingsalvage receptor binding epitope residues and having increased in vivohalf-life, see U.S. Pat. No. 5,869,046.

Diabodies are antibody fragments with two antigen-binding sites that maybe bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161;Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc.Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodiesare also described in Hudson et al. Nat. Med. 9:129-134 (2003).

Single-domain antibodies are antibody fragments comprising all or aportion of the heavy chain variable domain or all or a portion of thelight chain variable domain of an antibody. In certain embodiments, asingle-domain antibody is a human single-domain antibody (Domantis,Inc., Waltham, Mass.; see, e.g., U.S. Pat. No. 6,248,516 B1).

Antibody fragments can be made by various techniques, including but notlimited to proteolytic digestion of an intact antibody as well asproduction by recombinant host cells (e.g. E. coli or phage), asdescribed herein.

3. Chimeric and Humanized Antibodies

In certain embodiments, an antibody provided herein is a chimericantibody. Certain chimeric antibodies are described, e.g., in U.S. Pat.No. 4,816,567; and Morrison et al. Proc. Natl. Acad. Sci. USA,81:6851-6855 (1984)). In one example, a chimeric antibody comprises anon-human variable region (e.g., a variable region derived from a mouse,rat, hamster, rabbit, or non-human primate, such as a monkey) and ahuman constant region. In a further example, a chimeric antibody is a“class switched” antibody in which the class or subclass has beenchanged from that of the parent antibody. Chimeric antibodies includeantigen-binding fragments thereof.

In certain embodiments, a chimeric antibody is a humanized antibody.Typically, a non-human antibody is humanized to reduce immunogenicity tohumans, while retaining the specificity and affinity of the parentalnon-human antibody. Generally, a humanized antibody comprises one ormore variable domains in which HVRs, e.g., CDRs, (or portions thereof)are derived from a non-human antibody, and FRs (or portions thereof) arederived from human antibody sequences. A humanized antibody optionallywill also comprise at least a portion of a human constant region. Insome embodiments, some FR residues in a humanized antibody aresubstituted with corresponding residues from a non-human antibody (e.g.,the antibody from which the HVR residues are derived), e.g., to restoreor improve antibody specificity or affinity.

Humanized antibodies and methods of making them are reviewed, e.g., inAlmagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and arefurther described, e.g., in Riechmann et al., Nature 332:323-329 (1988);Queen et al., Proc. Nat'l Acad. Sci. USA 86:10029-10033 (1989); U.S.Pat. Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri etal., Methods 36:25-34 (2005) (describing specificity determining region(SDR) grafting); Padlan, Mol. Immunol. 28:489-498 (1991) (describing“resurfacing”); Dall'Acqua et al., Methods 36:43-60 (2005) (describing“FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimkaet al., Br. J. Cancer, 83:252-260 (2000) (describing the “guidedselection” approach to FR shuffling).

Human framework regions that may be used for humanization include butare not limited to: framework regions selected using the “best-fit”method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993)); frameworkregions derived from the consensus sequence of human antibodies of aparticular subgroup of light or heavy chain variable regions (see, e.g.,Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta etal. J. Immunol., 151:2623 (1993)); human mature (somatically mutated)framework regions or human germline framework regions (see, e.g.,Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)); and frameworkregions derived from screening FR libraries (see, e.g., Baca et al., J.Biol. Chem. 272:10678-10684 (1997) and Rosok et al., J. Biol. Chem.271:22611-22618 (1996)).

4. Human Antibodies

In certain embodiments, an antibody provided herein is a human antibody.Human antibodies can be produced using various techniques known in theart. Human antibodies are described generally in van Dijk and van deWinkel, Curr. Opin. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opin.Immunol. 20:450-459 (2008).

Human antibodies may be prepared by administering an immunogen to atransgenic animal that has been modified to produce intact humanantibodies or intact antibodies with human variable regions in responseto antigenic challenge. Such animals typically contain all or a portionof the human immunoglobulin loci, which replace the endogenousimmunoglobulin loci, or which are present extrachromosomally orintegrated randomly into the animal's chromosomes. In such transgenicmice, the endogenous immunoglobulin loci have generally beeninactivated. For review of methods for obtaining human antibodies fromtransgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). Seealso, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 describing XENOMOUSE™technology; U.S. Pat. No. 5,770,429 describing HUMAB® technology; U.S.Pat. No. 7,041,870 describing K-M MOUSE® technology, and U.S. PatentApplication Publication No. US 2007/0061900, describing VELOCIMOUSE®technology). Human variable regions from intact antibodies generated bysuch animals may be further modified, e.g., by combining with adifferent human constant region.

Human antibodies can also be made by hybridoma-based methods. Humanmyeloma and mouse-human heteromyeloma cell lines for the production ofhuman monoclonal antibodies have been described. (See, e.g., Kozbor J.Immunol., 133: 3001 (1984); Brodeur et al., Monoclonal AntibodyProduction Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc.,New York, 1987); and Boerner et al., J. Immunol., 147: 86 (1991).) Humanantibodies generated via human B-cell hybridoma technology are alsodescribed in Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562(2006). Additional methods include those described, for example, in U.S.Pat. No. 7,189,826 (describing production of monoclonal human IgMantibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue,26(4):265-268 (2006) (describing human-human hybridomas). Humanhybridoma technology (Trioma technology) is also described in Vollmersand Brandlein, Histology and Histopathology, 20(3):927-937 (2005) andVollmers and Brandlein, Methods and Findings in Experimental andClinical Pharmacology, 27(3):185-91 (2005).

Human antibodies may also be generated by isolating Fv clone variabledomain sequences selected from human-derived phage display libraries.Such variable domain sequences may then be combined with a desired humanconstant domain. Techniques for selecting human antibodies from antibodylibraries are described below.

5. Library-Derived Antibodies

Antibodies of the invention may be isolated by screening combinatoriallibraries for antibodies with the desired activity or activities. Forexample, a variety of methods are known in the art for generating phagedisplay libraries and screening such libraries for antibodies possessingthe desired binding characteristics. Such methods are reviewed, e.g., inHoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien etal., ed., Human Press, Totowa, N.J., 2001) and further described, e.g.,in the McCafferty et al., Nature 348:552-554; Clackson et al., Nature352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992);Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo,ed., Human Press, Totowa, N.J., 2003); Sidhu et al., J. Mol. Biol.338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093(2004); Fellouse, Proc. Natl. Acad. Sci. USA 101 (34): 12467-12472(2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004).

In certain phage display methods, repertoires of VH and VL genes areseparately cloned by polymerase chain reaction (PCR) and recombinedrandomly in phage libraries, which can then be screened forantigen-binding phage as described in Winter et al., Ann. Rev. Immunol.,12: 433-455 (1994). Phage typically display antibody fragments, eitheras single-chain Fv (scFv) fragments or as Fab fragments. Libraries fromimmunized sources provide high-affinity antibodies to the immunogenwithout the requirement of constructing hybridomas. Alternatively, thenaive repertoire can be cloned (e.g., from human) to provide a singlesource of antibodies to a wide range of non-self and also self antigenswithout any immunization as described by Griffiths et al., EMBO J, 12:725-734 (1993). Finally, naive libraries can also be made syntheticallyby cloning unrearranged V-gene segments from stem cells, and using PCRprimers containing random sequence to encode the highly variable CDR3regions and to accomplish rearrangement in vitro, as described byHoogenboom and Winter, J. Mol. Biol., 227: 381-388 (1992). Patentpublications describing human antibody phage libraries include, forexample: U.S. Pat. No. 5,750,373, and US Patent Publication Nos.2005/0079574, 2005/0119455, 2005/0266000, 2007/0117126, 2007/0160598,2007/0237764, 2007/0292936, and 2009/0002360.

Antibodies or antibody fragments isolated from human antibody librariesare considered human antibodies or human antibody fragments herein.

6. Multispecific Antibodies

In any one of the above aspects, the anti-CD3 antibody provided hereinis a multispecific antibody, for example, a bispecific antibody.Multispecific antibodies are monoclonal antibodies that have bindingspecificities for at least two different sites. In certain embodiments,bispecific antibodies may bind to two different epitopes of CD3 (e.g.,CD3ε or CD3γ). In certain embodiments, one of the binding specificitiesis for CD3 (e.g., CD3ε or CD3γ) and the other is for any other antigen(e.g., a second biological molecule, e.g., a cell surface antigen, e.g.,a tumor antigen). Accordingly, a bispecific anti-CD3 antibody may havebinding specificities for CD3 and a second biological molecule, such asa second biological molecule (e.g., a tumor antigen) listed in Table 1and described in U.S. Pub. No. 2010/0111856.

TABLE 1 Tumor antigen targets of the bispecific anti-CD3 antibodies ofthe invention CD20 CD79a ETBR IL13Ralpha2 M-CSF P2X5 SSX-2 0772P CD79bETV6- IL20Rα MCSP p53 SSX-4 AML1 fusion protein Adipophilin Cdc27 EZH2Intestinal carboxyl mdm-2 PAP STEAP1 esterase AIM-2 CDK4 FcRH1 IRTA2 MDPPAX5 STEAP1 ALDH1A1 CDKN2A FcRH2 Kallikrein 4 ME1 PBF STEAP2 alpha- CEAFcRH5 KIF20A Melan-A/ PMEL17 survivin actinin-4 MART-1 alpha- CLL1FLT3-ITD KK-LC-1 Meloe pml- SYT- foetoprotein RARalpha SSX1 or - fusionSSX2 fusion protein protein Amphiregulin CLPP FN1 KM-HN-1 MMP-2 PRAMETAG-1 ARTC1 COA-1 G250/ K-ras MMP-7 PRDX5 TAG-2 MN/ CAIX ASLG659 CPSFGAGE- LAGE-1 MPF PSCA Telomerase 1,2,8 ASPHD1 CRIPTO GAGE- LDLR- MRP4PSCA hlg TENB2 3,4,5,6,7 fucosyltransferaseAS- fusion protein B7-H4 Cw6GDNF- Lengsin MSG783 PSMA TGF-betaRII Ra1 BAFF-R CXCR5 GEDA LGR5 MUC1PTPRK TMEFF1 BAGE-1 CXORF61 GFRA1 LY64 MUC5AC RAB38/ TMEM118 NY-MEL-1BCLX (L) cyclin D1 glypican- Ly6E mucin RAGE-1 TMEM46 3 BCR- Cyclin-A1GnTVf Ly6G6D MUM-1f RBAF600 TRAG-3 ABL fusion protein (b3a2) beta- dek-gp100/ LY6K MUM-2 RET Triosephosphate catenin can fusion Pmel17isomerase protein BING-4 DKK1 GPC3 LYPD1 MUM-3 RGS5 TRP-1/gp75 B-RAF DR1GPNMB MAGE-A1 Myosin RhoC TRP-2 class I Brevican DR13 GPR172A MAGE-A10NA88-A RNF43 TRP2-INT2 CALCA E16 GPR19 MAGE-A12 Napi2b RNF43 TrpM4CASP-5 EDAR GPR54 MAGE-A2 NCA RU2AS Tyrosinase CASP-8 EFTUD2 HAVCR1MAGE-A3 neo-PAP SAGE tyrosinase CD19 Elongation HER2 MAGE-A4 NFYCsecernin 1 VEGF factor 2 CD21 ENAH (hMena) HER-2/ MAGE-A6 N-ras Sema 5bWT1 neu CD22 EpCAM HERV-K- MAGE-A9 NY-BR-1 SIRT2 XAGE- MEL 1b/GAGED2aCD33 EphA3 HLA-DOB MAGE-C1 NY- SLC35D3 EGFR- ESO-1/ T790M; LAGE-2 CD45EphB2R hsp70-2 MAGE-C2 OA1 SNRPD1 BMPR1B CD70 Epiregulin IDO1mammaglobin-A OGT SOX10 CD72 EGFR IGF2B3 MART2 OS-9 Sp17 EGFR- EGFR-EGFR- EGFR-L858R EGFR- EGFR- G719A G719C; G719S; S768I L861Q

The bispecific anti-CD3 antibody (e.g., any one of the anti-CD3antibodies described above) may have binding specificities for CD3 and asecond biological molecule such as a human leukocyte antigen(HLA)-peptide complex presented on the cell surface by MHC. Thebispecific anti-CD3 antibody (e.g., any one of the anti-CD3 antibodiesdescribed above) may have binding specificities for CD3 and a secondbiological molecule comprising a HLA-peptide complex selected from thegroup consisting of 0772P (CA125, MUC16; Genbank accession no. AF36148);adipophilin (perilipin-2, Adipose differentiation-related protein, ADRP,ADFP, MGC10598; NCBI Reference Sequence: NP_001113.2); AIM-2 (Absent InMelanoma 2, PYHIN4, Interferon-Inducible Protein AIM2; NCBI ReferenceSequence: NP_004824.1); ALDH1 A1 (Aldehyde Dehydrogenase 1 Family,Member A1, ALDH1, PUMB1, Retinaldehyde Dehydrogenase 1, ALDC, ALDH-E1,ALHDII, RALDH 1, EC 1.2.1.36, ALDH11, HEL-9, HEL-S-53e, HEL12, RALDH1,Acetaldehyde Dehydrogenase 1, Aldehyde Dehydrogenase 1, Soluble,Aldehyde Dehydrogenase, Liver Cytosolic, ALDH Class 1, EpididymisLuminal Protein 12, Epididymis Luminal Protein 9, Epididymis SecretorySperm Binding Protein Li 53e, Retinal Dehydrogenase 1, RalDH1, AldehydeDehydrogenase Family 1 Member A1, Aldehyde Dehydrogenase, Cytosolic, EC1.2.1; NCBI Reference Sequence: NP_000680.2); alpha-actinin-4 (ACTN4,Actinin, Alpha 4, FSGS1, Focal Segmental Glomerulosclerosis 1,Non-Muscle Alpha-Actinin 4, F-Actin Cross-Linking Protein, FSGS,ACTININ-4, Actinin Alpha4 Isoform, alpha-actinin-4; NCBI ReferenceSequence: NP_004915.2); alpha-fetoprotein (AFP, HPAFP, FETA,alpha-1-fetoprotein, alpha-fetoglobulin, Alpha-1-fetoprotein,Alpha-fetoglobulin, HP; GenBank: AAB58754.1); Amphiregulin (AREG, SDGF,Schwannoma-Derived Growth Factor, Colorectum Cell-Derived Growth Factor,AR, CRDGF; GenBank: AAA51781.1); ARTC1 (ART1, ADP-Ribosyltransferase 1,Mono(ADP-Ribosyl)Transferase 1, ADP-Ribosyltransferase C2 And C3Toxin-Like 1, ART2, CD296, RT6, ADP-Ribosyltransferase 2, GPI-LinkedNAD(P)(+)-Arginine ADP-Ribosyltransferase 1, EC 2.4.2.31, CD296 Antigen;NP); ASLG659; ASPHD1 (Aspartate Beta-Hydroxylase Domain Containing 1,Aspartate Beta-Hydroxylase Domain-Containing Protein 1, EC 1.14.11.-, EC1.14.11; GenBank: AAI44153.1); B7-H4 (VTCN1, V-Set Domain Containing TCell Activation Inhibitor 1, B7H4, B7 Superfamily Member 1, ImmuneCostimulatory Protein B7-H4, B7h.5, T-Cell Costimulatory Molecule B7x,B7S1, B7X, VCTN1, H4, B7 Family Member, PRO1291, B7 Family Member, H4, TCell Costimulatory Molecule B7x, V-Set Domain-Containing T-CellActivation Inhibitor 1, Protein B7S1; GenBank: AAZ17406.1); BAFF-R(TNFRSF13C, Tumor Necrosis Factor Receptor Superfamily, Member 13C,BAFFR, B-Cell-Activating Factor Receptor, BAFF Receptor, BLyS Receptor3, CVID4, BROMIX, CD268, B Cell-Activating Factor Receptor, prolixin,Tumor Necrosis Factor Receptor Superfamily Member 13C, BR3, CD268Antigen; NCBI Reference Sequence: NP_443177.1); BAGE-1; BCLX (L);BCR-ABL fusion protein (b3a2); beta-catenin (CTNNB1, Catenin(Cadherin-Associated Protein), Beta 1, 88 kDa, CTNNB, MRD19, Catenin(Cadherin-Associated Protein), Beta 1 (88 kD), armadillo, CateninBeta-1; GenBank: CAA61107.1); BING-4 (WDR46, WD Repeat Domain 46,C6orf11, BING4, WD Repeat-Containing Protein BING4, Chromosome 6 OpenReading Frame 11, FP221, UTP7, WD Repeat-Containing Protein 46; NP);BMPR1B (bone morphogenetic protein receptor-type IB, Genbank accessionno. NM_00120; NP); B-RAF (Brevican (BCAN, BEHAB, Genbank accession no.AF22905); Brevican (BCAN, Chondroitin Sulfate Proteoglycan 7,Brain-Enriched Hyaluronan-Binding Protein, BEHAB, CSPG7, BrevicanProteoglycan, Brevican Core Protein, Chondroitin Sulfate ProteoglycanBEHAB; GenBank: AAH27971.1); CALCA (Calcitonin-Related PolypeptideAlpha, CALC1, Calcitonin 1, calcitonin, Alpha-Type CGRP, CalcitoninGene-Related Peptide I, CGRP-I, CGRP, CGRP1, CT, KC,Calcitonin/Calcitonin-Related Polypeptide, Alpha, katacalcin; NP);CASP-5 (CASP5, Caspase 5, Apoptosis-Related Cysteine Peptidase, Caspase5, Apoptosis-Related Cysteine Protease, Protease ICH-3, Protease TY,ICE(rel)-III, ICE(rel)III, ICEREL-III, ICH-3, caspase-5, TY Protease, EC3.4.22.58, ICH3, EC 3.4.22; NP); CASP-8; CD19 (CD19—B-lymphocyte antigenCD19 isoform 2 precursor, B4, CVID3 [Homo sapiens], NCBI ReferenceSequence: NP_001761.3); CD20 (CD20—B-lymphocyte antigen CD20,membrane-spanning 4-domains, subfamily A, member 1, B1, Bp35, CD20,CVID5, LEU-16, MS4A2, S7; NCBI Reference Sequence: NP_690605.1); CD21(CD21 (CR2 (Complement receptor or C3DR (C3d/Epstein Barr virusreceptor) or Hs.73792 Genbank accession no. M2600); (CD22 (B-cellreceptor CD22-B isoform, BL-CAM, Lyb-8, Lyb8, SIGLEC-2, FLJ22814,Genbank accession No. AK02646); CD22; CD33 (CD33 Molecule, CD33 Antigen(Gp67), Sialic Acid Binding Ig-Like Lectin 3, Sialic Acid-BindingIg-Like Lectin 3, SIGLEC3, gp67, SIGLEC-3, Myeloid Cell Surface AntigenCD33, p67, Siglec-3, CD33 Antigen; GenBank: AAH28152.1); CD45; CD70(CD70—tumor necrosis factor (ligand) superfamily, member 7; surfaceantigen CD70; Ki-24 antigen; CD27 ligand; CD27-L; tumor necrosis factorligand superfamily member 7; NCBI Reference Sequence for species Homosapiens: NP_001243.1); CD72 (CD72 (B-cell differentiation antigen CD72,Lyb-; 359 aa, pl: 8.66, MW: 40225, TM: 1 [P] Gene Chromosome: 9p13.3,Genbank accession No. NP_001773); CD79a (CD79a (CD79A, CD79a,immunoglobulin-associated alpha, a B cell-specific protein thatcovalently interacts with Ig beta (CD79B) and forms a complex on thesurface with Ig M molecules, transduces a signal involved in B-celldifferentiation), pl: 4.84, MW: 25028 TM: 2 [P] Gene Chromosome:19q13.2, Genbank accession No. NP_001774.1); CD79b (CD79b (CD79B, CD79b,IGb (immunoglobulin-associated beta), B29, Genbank accession no.NM_000626 or 1103867); Cdc27 (Cell Division Cycle 27, D0S1430E,D17S978E, Anaphase Promoting Complex Subunit 3, Anaphase-PromotingComplex Subunit 3, ANAPC3, APC3, CDC27Hs, H-NUC, CDC27 Homolog, CellDivision Cycle 27 Homolog (S. Cerevisiae), HNUC, NUC2,Anaphase-Promoting Complex, Protein 3, Cell Division Cycle 27 Homolog,Cell Division Cycle Protein 27 Homolog, Nuc2 Homolog; GenBank:AAH11656.1); CDK4 (Cyclin-Dependent Kinase 4, Cell Division ProteinKinase 4, PSK-J3, EC 2.7.11.22, CMM3, EC 2.7.11; NCBI ReferenceSequence: NP_000066.1); CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A,MLM, CDKN2, MTS1, Cyclin-Dependent Kinase Inhibitor 2A (Melanoma, P16,Inhibits CDK4), Cyclin-Dependent Kinase 4 Inhibitor A, Multiple TumorSuppressor 1, CDK41, MTS-1, CMM2, P16, ARF, INK4, INK4A, P14, P14ARF,P16-INK4A, P161NK4, P161NK4A, P19, P19ARF, TP16, CDK4 InhibitorP16-INK4, Cell Cycle Negative Regulator Beta, p14ARF, p16-INK4,p16-INK4a, p161NK4A, p19ARF; NP); CEA; CLL1 (CLL-1 (CLEC12A, MICL, andDCAL, encodes a member of the C-type lectin/C-type lectin-like domain(CTL/CTLD) superfamily. Members of this family share a common proteinfold and have diverse functions, such as cell adhesion, cell-cellsignaling, glycoprotein turnover, and roles in inflammation and immuneresponse. The protein encoded by this gene is a negative regulator ofgranulocyte and monocyte function. Several alternatively splicedtranscript variants of this gene have been described, but thefull-length nature of some of these variants has not been determined.This gene is closely linked to other CTL/CTLD superfamily members in thenatural killer gene complex region on chromosome 12p13 (Drickamer KCurr. Opin. Struct. Biol. 9):585-90; van Rhenen A, et al., Blood110):2659-66; Chen C H, et al. Blood 107):1459-67; Marshall A S, et al.Eur. J. Immunol. 36):2159-69; Bakker A B, et al Cancer Res. 64:8443-50;Marshall A S, et al J. Biol. Chem. 279:14792-80. CLL-1 has been shown tobe a type II transmembrane receptor comprising a single C-typelectin-like domain (which is not predicted to bind either calcium orsugar), a stalk region, a transmembrane domain and a short cytoplasmictail containing an ITIM motif.); CLPP (Caseinolytic Mitochondrial MatrixPeptidase Proteolytic Subunit, Endopeptidase Clp, EC 3.4.21.92, PRLTS3,ATP-Dependent Protease CIpAP (E. Coli), CIpP (Caseinolytic Protease,ATP-Dependent, Proteolytic Subunit, E. Coli) Homolog, CIpP CaseinolyticPeptidase, ATP-Dependent, Proteolytic Subunit Homolog (E. Coli), CIpPCaseinolytic Protease, ATP-Dependent, Proteolytic Subunit Homolog (E.Coli), human, Proteolytic Subunit, ATP-Dependent Protease CIpAP,Proteolytic Subunit, Human, CIpP Caseinolytic Peptidase ATP-Dependent,Proteolytic Subunit, CIpP Caseinolytic Peptidase, ATP-Dependent,Proteolytic Subunit Homolog, CIpP Caseinolytic Protease, ATP-Dependent,Proteolytic Subunit Homolog, Putative ATP-Dependent CIp ProteaseProteolytic Subunit, Mitochondrial; NP); COA-1; CPSF; CRIPTO (CRIPTO(CR, CR1, CRGF, CRIPTO, TDGF1, teratocarcinoma-derived growth factor,Genbank accession no. NP_003203 or NM_00321); Cw6; CXCR5 CXCR5(Burkitt's lymphoma receptor 1, a G protein-coupled receptor that isactivated by the CXCL13 chemokine, functions in lymphocyte migration andhumoral defense, plays a role in HIV-2 infection and perhaps developmentof AIDS, lymphoma, myeloma, and leukemia); 372 aa, pl: 8.54 MW: 41959TM: 7 [P] Gene Chromosome: 11q23.3, Genbank accession No. NP_001707);CXORF61 CXORF61—chromosome X open reading frame 61 [Homo sapiens], NCBIReference Sequence: NP_001017978.1); cyclin D1 (CCND1, BCL1, PRAD1, D11S287E, B-Cell CLL/Lymphoma 1, B-Cell Lymphoma 1 Protein, BCL-1 Oncogene,PRAD1 Oncogene, Cyclin D1 (PRAD1: Parathyroid Adenomatosis 1),G1/S-Specific Cyclin D1, Parathyroid Adenomatosis 1, U21B31,G1/S-Specific Cyclin-D1, BCL-1; NCBI Reference Sequence: NP_444284.1);Cyclin-A1 (CCNA1, CT146, Cyclin A1; GenBank: AAH36346.1); dek-can fusionprotein; DKK1 (Dickkopf WNT Signaling Pathway Inhibitor 1, SK, hDkk-1,Dickkopf (Xenopus laevis) Homolog 1, Dickkopf 1 Homolog (Xenopuslaevis), DKK-1, Dickkopf 1 Homolog, Dickkopf Related Protein-1,Dickkopf-1 Like, Dickkopf-Like Protein 1, Dickkopf-Related Protein 1,Dickkopf-1, Dkk-1; GenBank: AAQ89364.1); DR1 (Down-Regulator OfTranscription 1, TBP-Binding (Negative Cofactor 2), Negative Cofactor2-Beta, TATA-Binding Protein-Associated Phosphoprotein, NC2, NC2-BETA,Protein Dr1, NC2-beta, Down-Regulator Of Transcription 1; NCBI ReferenceSequence: NP_001929.1); DR13 (Major Histocompatibility Complex, ClassII, DR Beta 1, HLA-DR1B, DRw10, DW2.2/DR2.2, SS1, DRB1, HLA-DRB, HLAClass II Histocompatibility Antigen, DR-1 Beta Chain, Human LeucocyteAntigen DRB1, Lymphocyte Antigen DRB1, MHC Class II Antigen, MHC ClassII HLA-DR Beta 1 Chain, MHC Class II HLA-DR-Beta Cell SurfaceGlycoprotein, MHC Class II HLA-DRw10-Beta, DR-1, DR-12, DR-13, DR-14,DR-16, DR-4, DR-5, DR-7, DR-8, DR-9, DR1, DR12, DR13, DR14, DR16, DR4,DR5, DR7, DR8, DR9, DRw11, DRw8, HLA-DRB2, Clone P2-Beta-3, MHC Class IIAntigen DRB1*1, MHC Class II Antigen DRB1*10, MHC Class II AntigenDRB1*11, MHC Class II Antigen DRB1*12, MHC Class II Antigen DRB1*13, MHCClass II Antigen DRB1*14, MHC Class II Antigen DRB1*15, MHC Class IIAntigen DRB1*16, MHC Class II Antigen DRB1*3, MHC Class II AntigenDRB1*4, MHC Class II Antigen DRB1*7, MHC Class II Antigen DRB1*8, MHCClass II Antigen DRB1*9; NP); E16 (E16 (LAT1, SLC7A5, Genbank accessionno. NM_00348); EDAR (EDAR—tumor necrosis factor receptor superfamilymember EDAR precursor, EDA-A1 receptor; downless homolog;ectodysplasin-A receptor; ectodermal dysplasia receptor; anhidroticectodysplasin receptor 1, DL; ECTD10A; ECTD10B; ED1R; ED3; ED5; EDA-A1R;EDA1R; EDA3; HRM1 [Homo sapiens]; NCBI Reference Sequence: NP_071731.1);EFTUD2 (Elongation Factor Tu GTP Binding Domain Containing 2, ElongationFactor Tu GTP-Binding Domain-Containing Protein 2, hSNU114, SNU114Homolog, U5 SnRNP-Specific Protein, 116 KDa, MFDGA, KIAA0031, 116 KD, U5SnRNP Specific Protein, 116 KDa U5 Small Nuclear RibonucleoproteinComponent, MFDM, SNRNP116, Snrp 116, Snu114, U5-116KD, SNRP116, U5-116KDa; GenBank: AAH02360.1); EGFR (Epidermal Growth Factor Receptor, ERBB,Proto-Oncogene C-ErbB-1, Receptor Tyrosine-Protein Kinase ErbB-1, ERBB1,HER1, EC 2.7.10.1, Epidermal Growth Factor Receptor (AvianErythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog),Erythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog (Avian), PIG61,Avian Erythroblastic Leukemia Viral (V-Erb-B) Oncogene Homolog, CellGrowth Inhibiting Protein 40, Cell Proliferation-Inducing Protein 61,mENA, EC 2.7.10; GenBank: AAH94761.1); EGFR-G719A; EGFR-G719C;EGFR-G719S; EGFR-L858R; EGFR-L861 Q; EGFR-S7681; EGFR-T790M; Elongationfactor 2 (EEF2, Eukaryotic Translation Elongation Factor 2, EF2,Polypeptidyl-TRNA Translocase, EF-2, SCA26, EEF-2; NCBI ReferenceSequence: NP_001952.1); ENAH (hMena) (Enabled Homolog (Drosophila),MENA, Mammalian Enabled, ENA, NDPP1, Protein Enabled Homolog; GenBank:AAH95481.1)—results for just “ENAH” not “ENAH (hMena)”; EpCAM(Epithelial Cell Adhesion Molecule, M4S1, MIC18, Tumor-AssociatedCalcium Signal Transducer 1, TACSTD1, TROP1, Adenocarcinoma-AssociatedAntigen, Cell Surface Glycoprotein Trop-1, Epithelial Glycoprotein 314,Major Gastrointestinal Tumor-Associated Protein GA733-2, EGP314, KSA,DIAR5, HNPCC8, Antigen Identified By Monoclonal Antibody AUA1, EGP-2,EGP40, ESA, KS1/4, MK-1, Human Epithelial Glycoprotein-2, MembraneComponent, Chromosome 4, Surface Marker (35 kD Glycoprotein), EGP,Ep-CAM, GA733-2, M1S2, CD326 Antigen, Epithelial Cell Surface Antigen,hEGP314, KS 1/4 Antigen, ACSTD1; GenBank: AAH14785.1); EphA3 (EPHReceptor A3, ETK1, ETK, TYRO4, HEK, Eph-Like Tyrosine Kinase 1,Tyrosine-Protein Kinase Receptor ETK1, EK4, EPH-Like Kinase 4, EC2.7.10.1, EPHA3, HEK4, Ephrin Type-A Receptor 3, Human Embryo Kinase 1,TYRO4 Protein Tyrosine Kinase, hEK4, Human Embryo Kinase,Tyrosine-Protein Kinase TYRO4, EC 2.7.10; GenBank: AAH63282.1); EphB2R;Epiregulin (EREG, ER, proepiregulin; GenBank: AA136405.1); ETBR (EDNRB,Endothelin Receptor Type B, HSCR2, HSCR, Endothelin ReceptorNon-Selective Type, ET-B, ET-BR, ETRB, ABCDS, WS4A, ETB, Endothelin BReceptor; NP); ETV6-AML1 fusion protein; EZH2 (Enhancer Of Zeste Homolog2 (Drosophila), Lysine N-Methyltransferase 6, ENX-1, KMT6 EC 2.1.1.43,EZH1, WVS, Enhancer Of Zeste (Drosophila) Homolog 2, ENX1, EZH2b, KMT6A,WVS2, Histone-Lysine N-Methyltransferase EZH2, Enhancer Of Zeste Homolog2, EC 2.1.1; GenBank: AAH10858.1); FcRH1 (FCRL1, Fc Receptor-Like 1,FCRH1, Fc Receptor Homolog 1, FcR-Like Protein 1, Immune ReceptorTranslocation-Associated Protein 5, IFGP1, IRTA5, hlFGP1, IFGP FamilyProtein 1, CD307a, Fc Receptor-Like Protein 1, ImmunoglobulinSuperfamily Fc Receptor, Gp42, FcRL1, CD307a Antigen; GenBank:AAH33690.1); FcRH2 (FCRL2, Fc Receptor-Like 2, SPAP1, SH2Domain-Containing Phosphatase Anchor Protein 1, Fc Receptor Homolog 2,FcR-Like Protein 2, Immunoglobulin Receptor Translocation-AssociatedProtein 4, FCRH2, IFGP4, IRTA4, IFGP Family Protein 4, SPAP1A, SPAP1B,SPAP1C, CD307b, Fc Receptor-Like Protein 2, Immune ReceptorTranslocation-Associated Protein 4, Immunoglobulin Superfamily FcReceptor, Gp42, SH2 Domain Containing Phosphatase Anchor Protein 1,FcRL2, CD307b Antigen; GenBank: AAQ88497.1); FcRH5 (FCRL5, FcReceptor-Like 5, IRTA2, Fc Receptor Homolog 5, FcR-Like Protein 5,Immune Receptor Translocation-Associated Protein 2, BXMAS1, FCRH5,CD307, CD307e, PRO820, Fc Receptor-Like Protein 5, ImmunoglobulinSuperfamily Receptor Translocation Associated 2 (IRTA2), FcRL5, CD307eAntigen; GenBank: AAI01070.1); FLT3-ITD; FN1 (Fibronectin 1,Cold-Insoluble Globulin, FN, Migration-Stimulating Factor, CIG, FNZ,GFND2, LETS, ED-B, FINC, GFND, MSF, fibronectin; GenBank: AAI43764.1);G250 (MN, CAIX, Carbonic Anhydrase IX, Carbonic Dehydratase,RCC-Associated Protein G250, Carbonate Dehydratase IX, Membrane AntigenMN, Renal Cell Carcinoma-Associated Antigen G250, CA-IX, P54/58N, pMW1,RCC-Associated Antigen G250, Carbonic Anhydrase 9; NP);—alias resultsfor “G250” not “G250/MN/CAIX”; GAGE-1,2,8; GAGE-3,4,5,6,7; GDNF-Ra1(GDNF family receptor alpha 1; GFRA1; GDNFR; GDNFRA; RETL1; TRNR1; RET1L; GDNFR-alpha1; GFR-ALPHA-; U95847; BC014962; NM_145793 NM_005264);GEDA (Genbank accession No. AY26076); GFRA1—GDNF family receptoralpha-1; GDNF receptor alpha-1; GDNFR-alpha-1; GFR-alpha-1; RET ligand1; TGF-beta-related neurotrophic factor receptor 1 [Homo sapiens];ProtKB/Swiss-Prot: P56159.2; glypican-3 (GPC3, Glypican 3, SDYS,Glypican Proteoglycan 3, Intestinal Protein OCI-5, GTR2-2, MXR7, SGBS1,DGSX, OCI-5. SGB, SGBS, Heparan Sulphate Proteoglycan, SecretedGlypican-3, OCI5; GenBank: AAH35972.1); GnTVf; gp100 (PMEL,Premelanosome Protein, SILV, D12S53E, PMEL17, SIL, Melanocyte ProteinPmel 17, Melanocytes Lineage-Specific Antigen GP100, Melanoma-AssociatedME20 Antigen, Silver Locus Protein Homolog, ME20-M, ME20M, P1, P100,Silver (Mouse Homolog) Like, Silver Homolog (Mouse), ME20, SI,Melanocyte Protein Mel 17, Melanocyte Protein PMEL, Melanosomal MatrixProteinl7, Silver, Mouse, Homolog Of; GenBank: AAC60634.1); GPC; GPNMB(Glycoprotein (Transmembrane) Nmb, Glycoprotein NMB, GlycoproteinNmb-Like Protein, osteoactivin, Transmembrane Glycoprotein HGFIN, HGFIN,NMB, Transmembrane Glycoprotein, Transmembrane Glycoprotein NMB;GenBank: AAH32783.1); GPR172A (G protein-coupled receptor 172A; GPCR41;FLJ11856; D15Ertd747e); NP_078807.1; NM_024531.3); GPR19 (Gprotein-coupled receptor 19; Mm.478; NP_006134.1; NM_006143.2); GPR54(KISS1 receptor; KISS1R; GPR54; HOT7T175; AXOR1; NP_115940.2;NM_032551.4); HAVCR1 (Hepatitis A Virus Cellular Receptor 1, T-CellImmunoglobulin Mucin Family Member 1, Kidney Injury Molecule 1, KIM-1,KIM1, TIM, TIM-1, TIM1, TIMD-1, TIMD1, T-Cell Immunoglobulin MucinReceptor 1, T-Cell Membrane Protein 1, HAVCR, HAVCR-1, T CellImmunoglobin Domain And Mucin Domain Protein 1, HAVcr-1, T-CellImmunoglobulin And Mucin Domain-Containing Protein 1; GenBank:AAH13325.1); HER2 (ERBB2, V-Erb-B2 Avian Erythroblastic Leukemia ViralOncogene Homolog 2, NGL, NEU, Neuro/Glioblastoma Derived OncogeneHomolog, Metastatic Lymph Node Gene 19 Protein, Proto-Oncogene C-ErbB-2,Proto-Oncogene Neu, Tyrosine Kinase-Type Cell Surface Receptor HER2, MLN19, p¹85erbB2, EC 2.7.10.1, V-Erb-B2 Avian Erythroblastic Leukemia ViralOncogene Homolog 2 (Neuro/Glioblastoma Derived Oncogene Homolog), CD340,HER-2, HER-2/neu, TKR1, C-Erb B2/Neu Protein, herstatin,Neuroblastoma/Glioblastoma Derived Oncogene Homolog, ReceptorTyrosine-Protein Kinase ErbB-2, V-Erb-B2 Erythroblastic Leukemia ViralOncogene Homolog 2, Neuro/Glioblastoma Derived Oncogene Homolog, MLN19,CD340 Antigen, EC 2.7.10; NP); HER-2/neu—alias of above; HERV-K-MEL;HLA-DOB (Beta subunit of MHC class II molecule (1a antigen) that bindspeptides and presents them to CD4+ T lymphocytes); 273 aa, pl: 6.56, MW:30820.TM: 1 [P] Gene Chromosome: 6p21.3, Genbank accession No.NP_002111); hsp70-2 (HSPA2, Heat Shock 70 kDa Protein 2, Heat Shock 70kD Protein 2, HSP70-3, Heat Shock-Related 70 KDa Protein 2, Heat Shock70 KDa Protein 2; GenBank: AAD21815.1); IDO1 (Indoleamine2,3-Dioxygenase 1, IDO, INDO, Indoleamine-Pyrrole 2,3-Dioxygenase,IDO-1, Indoleamine-Pyrrole 2,3 Dioxygenase, Indolamine 2,3 Dioxygenase,Indole 2,3 Dioxygenase, EC 1.13.11.52; NCBI Reference Sequence:NP_002155.1); IGF2B3; IL13Ralpha2 (IL13RA2, Interleukin 13 Receptor,Alpha 2, Cancer/Testis Antigen 19, Interleukin-13-Binding Protein,IL-13R-alpha-2, IL-13RA2, IL-13 Receptor Subunit Alpha-2, IL-13R SubunitAlpha-2, CD213A2, CT19, IL-13R, IL13BP, Interleukin 13 Binding Protein,Interleukin 13 Receptor Alpha 2 Chain, Interleukin-13 Receptor SubunitAlpha-2, IL13R, CD213a2 Antigen; NP); IL20Rα; Intestinal carboxylesterase; IRTA2 (alias of FcRH5); Kallikrein 4 (KLK4, Kallikrein-RelatedPeptidase 4, PRSS17, EMSP1, Enamel Matrix Serine Proteinase 1,Kallikrein-Like Protein 1, Serine Protease 17, KLK-L1, PSTS, AI2A1,Kallikrein 4 (Prostase, Enamel Matrix, Prostate), ARM1, EMSP,Androgen-Regulated Message 1, Enamel Matrix Serine Protease 1,kallikrein, kallikrein-4, prostase, EC 3.4.21.-, Prostase, EC 3.4.21;GenBank: AAX30051.1); KIF20A (Kinesin Family Member 20A, RAB6KIFL, RAB6Interacting, Kinesin-Like (Rabkinesin6), Mitotic a; LAGE-1;LDLR-fucosyltransferaseASfusion protein; Lengsin (LGSN, Lengsin, LensProtein With Glutamine Synthetase Domain, GLULD1, Glutamate-AmmoniaLigase Domain-Containing Protein 1, LGS, Glutamate-Ammonia Ligase(Glutamine Synthetase) Domain Containing 1, Glutamate-Ammonia Ligase(Glutamine Synthase) Domain Containing 1, Lens Glutamine Synthase-Like;GenBank: AAF61255.1); LGR5 (leucine-rich repeat-containing Gprotein-coupled receptor 5; GPR49, GPR6; NP_003658.1; NM_003667.2; LY64(Lymphocyte antigen 64 (RP10, type I membrane protein of the leucinerich repeat (LRR) family, regulates B-cell activation and apoptosis,loss of function is associated with increased disease activity inpatients with systemic lupus erythematosis); 661 aa, pl: 6.20, MW: 74147TM: 1 [P] Gene Chromosome: 5q12, Genbank accession No. NP_005573; Ly6E(lymphocyte antigen 6 complex, locus E; Ly67, RIG-E, SCA-2, TSA-;NP_002337.1; NM_002346.2); Ly6G6D (lymphocyte antigen 6 complex, locusG6D; Ly6-D, MEGT; NP_067079.2; NM_021246.2); LY6K (lymphocyte antigen 6complex, locus K; LY6K; HSJ001348; FLJ3522; NP_059997.3; NM_017527.3);LyPD1—LY6/PLAUR domain containing 1, PHTS [Homo sapiens], GenBank:AAH17318.1); MAGE-A1 (Melanoma Antigen Family A, 1 (Directs ExpressionOf Antigen MZ2-E, MAGE1, Melanoma Antigen Family A 1, MAGEA1, MelanomaAntigen MAGE-1, Melanoma-Associated Antigen 1, Melanoma-AssociatedAntigen MZ2-E, Antigen MZ2-E, Cancer/Testis Antigen 1.1, CT1.1, MAGE-1Antigen, Cancer/Testis Antigen Family 1, Member 1, Cancer/Testis AntigenFamily 1, Member 1, MAGE1A; NCBI Reference Sequence: NP_004979.3);MAGE-A10 (MAGEA10, Melanoma Antigen Family A, 10, MAGE10, MAGE-10Antigen, Melanoma-Associated Antigen 10, Cancer/Testis Antigen 1.10,CT1.10, Cancer/Testis Antigen Family 1, Member 10, Cancer/Testis AntigenFamily 1, Member 10; NCBI Reference Sequence: NP_001238757.1); MAGE-A12(MAGEA12, Melanoma Antigen Family A, 12, MAGE12, Cancer/Testis Antigen1.12, CT1.12, MAGE12F Antigen, Cancer/Testis Antigen Family 1, Member12, Cancer/Testis Antigen Family 1, Member 12, Melanoma-AssociatedAntigen 12, MAGE-12 Antigen; NCBI Reference Sequence: NP_001159859.1);MAGE-A2 (MAGEA2, Melanoma Antigen Family A, 2, MAGE2, Cancer/TestisAntigen 1.2, CT1.2, MAGEA2A, MAGE-2 Antigen, Cancer/Testis AntigenFamily 1, Member 2, Cancer/Testis Antigen Family 1, Member 2, MelanomaAntigen 2, Melanoma-Associated Antigen 2; NCBI Reference Sequence:NP_001269434.1); MAGE-A3 (MAGEA3, Melanoma Antigen Family A, 3, MAGE3,MAGE-3 Antigen, Antigen MZ2-D, Melanoma-Associated Antigen 3,Cancer/Testis Antigen 1.3, CT1.3, Cancer/Testis Antigen Family 1, Member3, HIP8, HYPD, MAGEA6, Cancer/Testis Antigen Family 1, Member 3; NCBIReference Sequence: NP_005353.1); MAGE-A4 (MAGEA4, Melanoma AntigenFamily A, 4, MAGE4, Melanoma-Associated Antigen 4, Cancer/Testis Antigen1.4, CT1.4, MAGE-4 Antigen, MAGE-41 Antigen, MAGE-X2 Antigen, MAGE4A,MAGE4B, Cancer/Testis Antigen Family 1, Member 4, MAGE-41, MAGE-X2,Cancer/Testis Antigen Family 1, Member 4; NCBI Reference Sequence:NP_001011550.1); MAGE-A6 (MAGEA6, Melanoma Antigen Family A, 6, MAGE6,MAGE-6 Antigen, Melanoma-Associated Antigen 6, Cancer/Testis Antigen1.6, CT1.6, MAGE3B Antigen, Cancer/Testis Antigen Family 1, MelanomaAntigen Family A 6, Member 6, MAGE-3b, MAGE3B, Cancer/Testis AntigenFamily 1, Member 6; NCBI Reference Sequence: NP_787064.1); MAGE-A9(MAGEA9, Melanoma Antigen Family A, 9, MAGE9, MAGE-9 Antigen,Melanoma-Associated Antigen 9, Cancer/Testis Antigen 1.9, CT1.9,Cancer/Testis Antigen Family 1, Member 9, Cancer/Testis Antigen Family1, Member 9, MAGEA9A; NCBI Reference Sequence: NP_005356.1); MAGE-C1(MAGEC1, Melanoma Antigen Family C, 1, Cancer/Testis Antigen 7.1, CT7.1,MAGE-C1 Antigen, Cancer/Testis Antigen Family 7, Member 1, CT7,Cancer/Testis Antigen Family 7, Member 1, Melanoma-Associated AntigenC1; NCBI Reference Sequence: NP_005453.2); MAGE-C2 (MAGEC2, MelanomaAntigen Family C, 2, MAGEE1, Cancer/Testis Antigen 10, CT10, HCA587,Melanoma Antigen, Family E, 1, Cancer/Testis Specific, HepatocellularCarcinoma-Associated Antigen 587, MAGE-C2 Antigen, MAGE-E1 Antigen,Hepatocellular Cancer Antigen 587, Melanoma-Associated Antigen C2; NCBIReference Sequence: NP_057333.1); mammaglobin-A (SCGB2A2, Secretoglobin,Family 2A, Member 2, MGB1, Mammaglobin 1, UGB2, Mammaglobin A,mammaglobin-A, Mammaglobin-1, Secretoglobin Family 2A Member 2; NP);MART2 (HHAT, Hedgehog Acyltransferase, SKI1, Melanoma Antigen RecognizedBy T-Cells 2, Skinny Hedgehog Protein 1, Skn, Melanoma AntigenRecognized By T Cells 2, Protein-Cysteine N-Palmitoyltransferase HHAT,EC 2.3.1.-; GenBank: AAH39071.1); M-CSF (CSF1, Colony Stimulating Factor1 (Macrophage), MCSF, CSF-1, lanimostim, Macrophage Colony-StimulatingFactor 1, Lanimostim; GenBank: AAH21117.1); MCSP (SMCP, SpermMitochondria-Associated Cysteine-Rich Protein, MCS, MitochondrialCapsule Selenoprotein, HSMCSGEN1, Sperm Mitochondrial-AssociatedCysteine-Rich Protein; NCBI Reference Sequence: NP_109588.2);XAGE-1b/GAGED2a; WT1 (Wilms Tumor 1, WAGR, GUD, WIT-2, WT33,Amino-Terminal Domain Of EWS, NPHS4, Last Three Zinc Fingers Of TheDNA-Binding Domain Of WT1, AWT1, Wilms Tumor Protein, EWS-WT1; GenBank:AAB33443.1); VEGF; Tyrosinase (TYR; OCAIA; OCA1A; tyrosinase; SHEP;NP_000363.1; NM_000372.4; GenBank: AAB60319.1); TrpM4 (BR22450,FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel,subfamily M, member 4, Genbank accession no. NM_01763); TRP2-INT2;TRP-2; TRP-1/gp75 (Tyrosinase-Related Protein 1,5,6-Dihydroxyindole-2-Carboxylic Acid Oxidase, CAS2, CATB, TYRP, OCA3,Catalase B, b-PROTEIN, Glycoprotein 75, EC 1.14.18., Melanoma AntigenGp75, TYRP1, TRP, TYRRP, TRP1, SHEP11, DHICA Oxidase, EC 1.14.18, GP75,EC 1.14.18.1; Triosephosphate isomerase (Triosephosphate isomerase 1,TPID, Triose-Phosphate Isomerase, HEL-S-49, TIM, Epididymis SecretoryProtein Li 49, TPI, Triosephosphate Isomerase, EC 5.3.1.1; TRAG-3 (CSAGFamily Member 2, Cancer/Testis Antigen Family 24, CSAG3B, Member 2, CSAGFamily Member 3B, Cancer/Testis Antigen Family 24 Member 2,Cancer/Testis Antigen 24.2, Chondrosarcoma-Associated Gene 2/3 Protein,Taxol-Resistant-Associated Gene 3 Protein, Chondrosarcoma-AssociatedGene 2/3 Protein-Like, CT24.2, Taxol Resistance Associated Gene 3,TRAG-3, CSAG3A, TRAG3; TMEM46 (shisa homolog 2 (Xenopus laevis); SHISA;NP_001007539.1; NM_001007538.1; TMEM118 (ring finger protein,transmembrane2; RNFT2; FLJ1462; NP_001103373.1; NM_001109903.1; TMEFF1(transmembrane protein with EGF-like and two follistatin-like domains 1;Tomoregulin-; H7365; C9orf2; C9ORF2; U19878; X83961; NM_080655;NM_003692; TGF-betaRII (TGFBR2, Transforming Growth Factor, BetaReceptor II (70/80 kDa), TGFbeta-RII, MFS2, tbetaR-II, TGFR-2, TGF-BetaReceptor Type IIB, TGF-Beta Type II Receptor, TGF-Beta Receptor Type-2,EC 2.7.11.30, Transforming Growth Factor Beta Receptor Type IIC, AAT3,TbetaR-II, Transforming Growth Factor, Beta Receptor II (70-80 kD),TGF-Beta Receptor Type II, FAA3, Transforming Growth Factor-BetaReceptor Type II, LDS1B, HNPCC6, LDS2B, LDS2, RIIC, EC 2.7.11, TAAD2;TENB2 (TMEFF2, tomoregulin, TPEF, HPP1, TR, putative transmembraneproteoglycan, related to the EGF/heregulin family of growth factors andfollistatin); 374 aa, NCBI Accession: AAD55776, AAF91397, AAG49451, NCBIRefSeq: NP_057276; NCBI Gene: 23671; OMIM: 605734; SwissProt Q9UIK5;Genbank accession No. AF179274; AY358907, CAF85723, CQ782436; TAG-2;TAG-1 (Contactin 2 (Axonal), TAG-1, AXT, Axonin-1 Cell AdhesionMolecule, TAX, Contactin 2 (transiently Expressed), TAX1, Contactin-2,Axonal Glycoprotein TAG-1, Transiently-Expressed Axonal Glycoprotein,Transient Axonal Glycoprotein, Axonin-1, TAX-1, TAG1, FAME5; PRF:444868); SYT-SSX1 or -SSX2 fusion protein; survivin; STEAP2 (HGNC_8639,IPCA-1, PCANAP1, STAMP1, STEAP2, STMP, prostate cancer associated gene1, prostate cancer associated protein 1, six transmembrane epithelialantigen of prostate 2, six transmembrane prostate protein, Genbankaccession no. AF45513; STEAP1 (six transmembrane epithelial antigen ofprostate, Genbank accession no. NM_01244; SSX-4; SSX-2 (SSX2, SynovialSarcoma, X Breakpoint2, X Breakpoint 2, SSX, X Breakpoint 2B,Cancer/Testis Antigen 5.2, X-Chromosome-Related 2, Tumor AntigenHOM-MEL-40, CT5.2, HD21, Cancer/Testis Antigen Family 5, HOM-MEL-40,Isoform B, Cancer/Testis Antigen Family 5 member 2a, member 2a, ProteinSSX2, Sarcoma, Sarcoma, Synovial, X-Chromosome-Related 2, synovial,Synovial Sarcoma, X Breakpoint 2B, Synovial Sarcomam, SSX2A; Sp17; SOX10(SRY (Sex Determining Region Y)-Box 10, mouse, PCWH, DOM, WS4, WS2E,WS4C, Dominant Megacolon, mouse, Human Homolog Of, Dominant Megacolon,SRY-Related HMG-Box Gene 10, Human Homolog Of, transcription FactorSOX-10; GenBank: CAG30470.1); SNRPD1 (Small Nuclear RibonucleoproteinD1, Small Nuclear Ribonucleoprotein D1, Polypeptide 16 kDa, Polypeptide(16 kD), SNRPD, HsT2456, Sm-D1, SMD1, Sm-D Autoantigen, Small NuclearRibonucleoprotein D1 Polypeptide 16 kDa Pseudogene, SnRNP Core ProteinD1, Small Nuclear Ribonucleoprotein Sm D1; SLC35D3 (Solute CarrierFamily 35, Member D3, FRCL1, Fringe Connection-Like Protein 1,bA55K22.3, Frc, Fringe-Like 1, Solute Carrier Family 35 Member D3; NCBIGenBank: NC_000006.11 NC_018917.2 NT_025741.16); SIRT2 (Sirtuin 2,NAD-Dependent Deacetylase Sirtuin-2, SIRL2, Silent Information Regulator2, Regulatory Protein SIR2 Homolog 2, Sir2-Related Protein Type 2,SIR2-Like Protein 2, Sirtuin Type 2, Sirtuin (Silent Mating TypeInformation Regulation 2 Homolog) 2 (S. Cerevisiae), Sirtuin-2, Sirtuin(Silent Mating Type Information Regulation 2, S. Cerevisiae, Homolog) 2,EC 3.5.1., SIR2; GenBank: AAK51133.1); Sema 5b (FLJ10372, KIAA1445,Mm.42015, SEMA5B, SEMAG, Semaphorin 5b Hlog, sema domain, seventhrombospondin repeats (type 1 and type 1-like), transmembrane domain(TM) and short cytoplasmic domain, (semaphorin) 5B, Genbank accessionno.

AB04087; secernin 1 (SCRN1, SES1, KIAA0193, secerin-1; GenBank:EAL24458.1); SAGE (SAGE1, Sarcoma Antigen 1, Cancer/Testis Antigen 14,CT14, Putative Tumor Antigen; NCBI Reference Sequence: NP_061136.2);RU2AS (KAAG1, Kidney Associated Antigen 1, RU2AS, RU2 Antisense GeneProtein, Kidney-Associated Antigen 1; GenBank: AAF23613.1); RNF43—E3ubiquitin-protein ligase RNF43 precursor [Homo sapiens], RNF124; URCC;NCBI Reference Sequence: NP_060233.3; RhoC (RGS5 (Regulator Of G-ProteinSignaling 5, MSTP032, Regulator Of G-Protein Signalling 5, MSTP092,MST092, MSTP106, MST106, MSTP129, MST129; GenBank: AAB84001.1); RET (retproto-oncogene; MEN2A; HSCR1; MEN2B; MTC1; PTC; CDHF12; Hs.168114;RET51; RET-ELE; NP_066124.1; NM_020975.4); RBAF600 (UBR4, UbiquitinProtein Ligase E3 Component N-Recognin 4, Zinc Finger, UBR1 Type 1,ZUBR1, E3 Ubiquitin-Protein Ligase UBR4, RBAF600, 600 KDa RetinoblastomaProtein-Associated Factor, Zinc Finger UBR1-Type Protein 1, EC 6.3.2.,N-recognin-4, KIAA0462, p600, EC 6.3.2, KIAA1307; GenBank: AAL83880.1);RAGE-1 (MOK, MOK Protein Kinase, Renal Tumor Antigen, RAGE, MAPK/MAK/MRKOverlapping Kinase, Renal Tumor Antigen 1, Renal Cell Carcinoma Antigen,RAGE-1, EC 2.7.11.22, RAGE1; UniProtKB/Swiss-Prot: Q9UQ07.1);RAB38/NY-MEL-1 (RAB38, NY-MEL-1, RAB38, Member RAS Oncogene Family,Melanoma Antigen NY-MEL-1, Rab-Related GTP-Binding Protein, Ras-RelatedProtein Rab-38, rrGTPbp; GenBank: AAH15808.1); PTPRK (DJ480J14.2.1(Protein Tyrosine Phosphatase, Receptor Type, K R-PTP-KAPPA, ProteinTyrosine Phosphatase Kappa, Protein Tyrosine Phosphatase Kappa), ProteinTyrosine Phosphatase, Receptor Type, K, Protein-Tyrosine PhosphataseKappa, Protein-Tyrosine Phosphatase, Receptor Type, Kappa, R-PTP-kappa,Receptor-Type Tyrosine-Protein Phosphatase Kappa, EC 3.1.3.48, PTPK;GenBank: AAI44514.1); PSMA; PSCA hIg (2700050C12Rik, C530008016Rik,RIKEN cDNA 2700050C12, RIKEN cDNA 2700050C12 gene, Genbank accession no.AY358628); PSCA (Prostate stem cell antigen precursor, Genbank accessionno. AJ29743; PRDX5 (Peroxiredoxin 5, EC 1.11.1.15, TPx Type VI, B166,Antioxidant Enzyme B166, HEL-S-55, Liver Tissue 2D-Page Spot 71B, PMP20,Peroxisomal Antioxidant Enzyme, PRDX6, Thioredoxin Peroxidase PMP20,PRXV, AOEB166, Epididymis Secretory Protein Li 55, Alu Co-Repressor 1,Peroxiredoxin-5, Mitochondrial, Peroxiredoxin V, prx-V, ThioredoxinReductase, Prx-V, ACR1, Alu Corepressor, PLP; GenBank: CAG33484.1);PRAME (Preferentially Expressed Antigen In Melanoma, PreferentiallyExpressed Antigen Of Melanoma, MAPE, OIP-4, OIPA, CT130, Cancer/TestisAntigen 130, Melanoma Antigen Preferentially Expressed In Tumors,Opa-Interacting Protein 4, Opa-Interacting Protein OIP4; GenBank:CAG30435.1); pml-RARalpha fusion protein; PMEL17 (silver homolog; SILV;D12S53E; PMEL17; SI; SIL); ME20; gp10 BC001414; BT007202; M32295;M77348; NM_006928; PBF (ZNF395, Zinc Finger Protein 395, PRF-1,Huntington disease regulatory, HD Gene Regulatory Region-BindingProtein, Region-Binding Protein 2, Protein 2, Papillomavirus RegulatoryFactor 1, HD-Regulating Factor 2, Papillomavirus-Regulatory Factor,PRF1, HDBP-2, Si-1-8-14, HDBP2, Huntington'S Disease Gene RegulatoryRegion-Binding Protein 2, HDRF-2, Papillomavirus Regulatory FactorPRF-1, PBF; GenBank: AAH01237.1); PAX5 (Paired Box 5, Paired BoxHomeotic Gene 5, BSAP, Paired Box Protein Pax-5, B-Cell Lineage SpecificActivator, Paired Domain Gene 5, Paired Box Gene 5 (B-Cell LineageSpecific Activator Protein), B-Cell-Specific Transcription Factor,Paired Box Gene 5 (B-Cell Lineage Specific Activator); PAP (REG3A,Regenerating Islet-Derived 3 Alpha, INGAP, PAP-H, HepatointestinalPancreatic Protein, PBBCGF, Human Proislet Peptide, REG-III,Pancreatitis-Associated Protein 1, Reg3, Reg III-Alpha,hepatocarcinoma-intestine-pancreas, Regenerating Islet-Derived ProteinIII-Alpha, Pancreatic Beta Cell Growth Factor, HIP, PAP HomologousProtein, HIP/PAP, Proliferation-Inducing Protein 34, PAP1,Proliferation-Inducing Protein 42, REG-3-alpha, RegeneratingIslet-Derived Protein 3-Alpha, Pancreatitis-Associated Protein; GenBank:AAH36776.1); p53 (TP53, Tumor Protein P53, TPR53, P53, Cellular TumorAntigen P53, Antigen NY-CO-13, Mutant Tumor Protein 53, PhosphoproteinP53, P53 Tumor Suppressor, BCC7, Transformation-Related Protein 53,LFS1, tumor Protein 53, Li-Fraumeni Syndrome, Tumor Suppressor P53; P2X5(Purinergic receptor P2X ligand-gated ion channel 5, an ion channelgated by extracellular ATP, may be involved in synaptic transmission andneurogenesis, deficiency may contribute to the pathophysiology ofidiopathic detrusor instability); 422 aa), pl: 7.63, MW: 47206 TM: 1 [P]Gene Chromosome: 17p13.3, Genbank accession No. NP_002552; OGT (O-LinkedN-Acetylglucosamine (GlcNAc) Transferase, O-GlcNAc Transferase P110Subunit, O-Linked N-Acetylglucosamine (GlcNAc) Transferase(UDP—N-Acetylglucosamine:Polypeptide-N-Acetylglucosaminyl Transferase,UDP—N-Acetylglucosamine-Peptide N-Acetylglucosaminyltransferase 110 KDaSubunit, UDP—N-Acetylglucosamine:Polypeptide-N-AcetylglucosaminylTransferase, Uridinediphospho-N-Acetylglucosamine:PolypeptideBeta-N-Acetylglucosaminyl Transferase, O-GlcNAc Transferase SubunitP110, EC 2.4.1.255, O-Linked N-Acetylglucosamine Transferase 110 KDaSubunit, EC 2.4.1, HRNT1, EC 2.4.1.186, O-GLCNAC; GenBank: AAH38180.1);OA1 (Osteoarthritis QTL 1, OASD; GenBank: CAA88742.1); NY-ESO-1/LAGE-2(Cancer/Testis Antigen 1B, CTAG1B, NY-ESO-1, LAGE-2, ESO1, CTAG1, CTAG,LAGE2B, Cancer/Testis Antigen 1, Autoimmunogenic Cancer/Testis AntigenNY-ESO-1, Ancer Antigen 3, Cancer/Testis Antigen 6.1, New YorkEsophageal Squamous Cell Carcinoma 1, L Antigen Family Member 2, LAGE2,CT6.1, LAGE2A; GenBank: AAI30365.1); NY-BR-1 (ANKRD30A, Ankyrin RepeatDomain 30A, Breast Cancer Antigen NY-BR-1, Serologically Defined BreastCancer Antigen NY-BR-1, Ankyrin Repeat Domain-Containing Protein 30A;NCBI Reference Sequence: NP_443723.2); N-ras (NRAS, Neuroblastoma RASViral (V-Ras) Oncogene Homolog, NRAS1, Transforming Protein N-Ras,GTPase NRas, ALPS4, N-Ras Protein Part 4, NS6, Oncogene Homolog, HRAS1;GenBank: AAH05219.1); NFYC (Nuclear Transcription Factor Y, Gamma, HAP5,HSM, Nuclear Transcription Factor Y Subunit C, Transactivator HSM-1/2,CCAAT Binding Factor Subunit C, NF-YC, CCAAT Transcription BindingFactor Subunit Gamma, CAAT Box DNA-Binding Protein Subunit C, Histone H1Transcription Factor Large Subunit 2A, CBFC, Nuclear TranscriptionFactor Y Subunit Gamma, CBF-C, Transactivator HSM-1, H1TF2A,Transcription Factor NF-Y, C Subunit; neo-PAP (PAPOLG, Poly(A)Polymerase Gamma, Neo-Poly(A) Polymerase, Nuclear Poly(A) PolymeraseGamma, Polynucleotide Adenylyltransferase Gamma, SRP RNA 3′ AdenylatingEnzyme/Pap2, PAP-gamma, Neo-PAP, SRP RNA 3′-Adenylating Enzyme, PAP2, EC2.7.7.19, PAPG; NCBI Reference Sequence: NP_075045.2); NCA (CEACAM6,Genbank accession no. M1872); Napi3b (NAPI-3B, NPTIIb, SLC34A2, solutecarrier family 34 (sodium phosphate), member 2, type II sodium-dependentphosphate transporter 3b, Genbank accession no. NM_00642); Myosin classI; MUM-3; MUM-2 (TRAPPC1, Trafficking Protein Particle Complex 1, BET5,BET5 Homolog, MUM2, Melanoma Ubiquitous Mutated 2, Multiple MyelomaProtein 2, Trafficking Protein Particle Complex Subunit 1; MUM-1f; Mucin(MUC1, Mucin 1, Cell Surface Associated, PEMT, PUM, CA 15-3, MCKD1,ADMCKD, Medullary Cystic Kidney Disease 1 (Autosomal Dominant), ADMCKD1,Mucin 1, Transmembrane, CD227, Breast Carcinoma-Associated Antigen DF3,MAM6, Cancer Antigen 15-3, MCD, Carcinoma-Associated Mucin, MCKD, KrebsVon Den Lungen-6, MUC-1/SEC, Peanut-Reactive Urinary Mucin, MUC1/ZD,Tumor-Associated Epithelial Membrane Antigen, DF3 Antigen,Tumor-Associated Mucin, episialin, EMA, H23 Antigen, H23AG, Mucin-1,KL-6, Tumor Associated Epithelial Mucin, MUC-1, Episialin, PEM, CD227Antigen; UniProtKB/Swiss-Prot: P15941.3); MUC5AC (Mucin 5AC, OligomericMucus/Gel-Forming, Tracheobronchial Mucin, MUC5, TBM, Mucin 5, SubtypesA And C, Tracheobronchial/Gastric, leB, Gastric Mucin, Mucin 5AC,Oligomeric Mucus/Gel-Forming Pseudogene, Lewis B Blood Group Antigen,LeB, Major Airway Glycoprotein, MUC-5AC, Mucin-5 Subtype AC,Tracheobronchial; MUC1 (Mucin 1, Cell Surface Associated, PEMT, PUM, CA15-3, MCKD1, ADMCKD, Medullary Cystic Kidney Disease 1 (AutosomalDominant), ADMCKD1, Mucin 1, Transmembrane, CD227, BreastCarcinoma-Associated Antigen DF3, MAM6, Cancer Antigen 15-3, MCD,Carcinoma-Associated Mucin, MCKD, Krebs Von Den Lungen-6, MUC-1/SEC,Peanut-Reactive Urinary Mucin, MUC-1/X, Polymorphic Epithelial Mucin,MUC1/ZD, Tumor-Associated Epithelial Membrane Antigen, DF3 Antigen,Tumor-Associated Mucin, episialin, EMA, h23 Antigen, H23AG, mucin-1,KL-6, Tumor Associated Epithelial Mucin, MUC-1, Episialin, PEM, CD227Antigen; MSG783 (RNF124, hypothetical protein FLJ20315, Genbankaccession no. NM-01776; MRP4—multidrug resistance-associated protein 4isoform 3, MOAT-B; MOATB [Homo sapiens]; NCBI Reference Sequence:NP_001288758.1; MPF (MPF, MSLN, SMR, megakaryocyte potentiating factor,mesothelin, Genbank accession no. NM_00582; MMP-7 (MMP7, matrilysin,MPSL1, matrin, Matrix Metalloproteinase 7 (Matrilysin, Uterine), UterineMatrilysin, Matrix Metalloproteinase-7, EC 3.4.24.23, Pump-1 Protease,Matrin, Uterine Metalloproteinase, PUMP1, MMP-7, EC 3.4.24, PUMP-1;GenBank: AAC37543.1); MMP-2 (MMP2, Matrix Metallopeptidase 2 (GelatinaseA, 72 kDa Gelatinase, 72 kDa Type IV Collagenase), MONA, CLG4A, MatrixMetalloproteinase 2 (Gelatinase A, 72 kD Gelatinase, 72 kD Type IVCollagenase), CLG4, 72 kDa Gelatinase, 72 kDa Type IV Collagenase),Matrix Metalloproteinase-2, MMP-II, 72 KDa Gelatinase, Collagenase TypeIV-A, MMP-2, Matrix Metalloproteinase-II, TBE-1, Neutrophil Gelatinase,EC 3.4.24.24, EC 3.4.24; GenBank: AAH02576.1); and Meloe.

For example, in some instances, an anti-CD3 antibody having a firstbinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequenceof SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ IDNO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO:6, such as 40G5c, may have a second binding domain that binds to CD20.The second binding domain that binds to CD20 may, for example, compriseat least one, two, three, four, five, or six hypervariable regions(HVRs) selected from (a) HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ IDNO: 158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:159; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds CD20comprises at least one (e.g., 1, 2, 3, or 4) of heavy chain frameworkregions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQID NOs: 557-560, respectively, and/or at least one (e.g., 1, 2, 3, or 4)of the light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4comprising the sequences of SEQ ID NOs: 561-564, respectively. In someinstances, the second binding domain that binds to CD20 may, forexample, comprise (a) a VH domain comprising an amino acid sequencehaving at least 90% sequence identity (e.g., at least 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequenceof, SEQ ID NO: 266; (b) a VL domain comprising an amino acid sequencehaving at least 90% sequence identity (e.g., at least 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or the sequenceof, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VL domain as in(b), such as possessed by the anti-CD20 antibody, 2H7.v16 (described inU.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds FcRH5 comprises at least one (e.g., 1, 2, 3,or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4comprising the sequences of SEQ ID NOs: 565-568, respectively, and/or atleast one (e.g., 1, 2, 3, or 4) of the light chain framework regionsFR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs:569-572, respectively. In some instances, the second binding domain thatbinds to FcRH5 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 268; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds HER2 comprises at least one (e.g., 1,2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, andFR-H4 comprising the sequences of SEQ ID NOs: 549-552, respectively,and/or at least one (e.g., 1, 2, 3, or 4) of the light chain frameworkregions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQID NOs: 553-556, respectively. In some instances, the second bindingdomain that binds to HER2 may, for example, comprise (a) a VH domaincomprising an amino acid sequence having at least 90% sequence identity(e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity) to, or the sequence of, SEQ ID NO: 270; (b) a VL domaincomprising an amino acid sequence having at least 90% sequence identity(e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity) to, or the sequence of, SEQ ID NO: 271; or (c) a VH domain asin (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds HER2 comprises at least one (e.g., 1, 2, 3, or4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4comprising the sequences of SEQ ID NOs: 597-600, respectively, and/or atleast one (e.g., 1, 2, 3, or 4) of the light chain framework regionsFR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs:601-604, respectively. In some instances, the second binding domain thatbinds to HER2 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 593; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds HER2 comprises at least one (e.g., 1, 2, 3, or4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4comprising the sequences of SEQ ID NOs: 605-608, respectively, and/or atleast one (e.g., 1, 2, 3, or 4) of the light chain framework regionsFR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs:609-612, respectively. In some instances, the second binding domain thatbinds to HER2 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 595; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds LYPD1 comprises at least one (e.g., 1,2, 3, or 4) of heavy chain framework regions FR-H1, FR-H2, FR-H3, andFR-H4 comprising the sequences of SEQ ID NOs: 573-576, respectively,and/or at least one (e.g., 1, 2, 3, or 4) of the light chain frameworkregions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQID NOs: 577-580, respectively. In some instances, the second bindingdomain that binds to LYPD1 may, for example, comprise (a) a VH domaincomprising an amino acid sequence having at least 90% sequence identity(e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity) to, or the sequence of, SEQ ID NO: 272; (b) a VL domaincomprising an amino acid sequence having at least 90% sequence identity(e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity) to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain asin (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6, such as40G5c, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v1, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 13; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v2, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 14, such as38E4v3, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 15, such as38E4v4, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 16, such as38E4v5, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 17; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v6, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 18; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v7, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 19; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v8, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 20; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 12, such as38E4v9, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 7; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ IDNO: 21; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 10;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 11; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22, such as38E4c, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to FcRH5. Thesecond binding domain that binds to FcRH5 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to LYPD1. Thesecond binding domain that binds to LYPD1 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 24; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v9, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to FcRH5. Thesecond binding domain that binds to FcRH5 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to LYPD1. Thesecond binding domain that binds to LYPD1 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 29; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1v1, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to CD20. Thesecond binding domain that binds to CD20 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to FcRH5. Thesecond binding domain that binds to FcRH5 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to HER2. Thesecond binding domain that binds to HER2 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to HER2. Thesecond binding domain that binds to HER2 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to HER2. Thesecond binding domain that binds to HER2 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to LYPD1. Thesecond binding domain that binds to LYPD1 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 23; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 30; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 25; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:26; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 27; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 28, such asUCHT1vM1, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to FcRH5. Thesecond binding domain that binds to FcRH5 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b). In some instances, ananti-CD3 antibody having a first binding domain comprising at least one,two, three, four, five, or six hypervariable regions (HVRs) selectedfrom (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 31; (b)HVR-H2 comprising the amino acid sequence of SEQ ID NO: 32; (c) HVR-H3comprising the amino acid sequence of SEQ ID NO: 33; (d) HVR-L1comprising the amino acid sequence of SEQ ID NO: 34; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 35; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 36, such as SP34v52,may have a second binding domain that binds to LYPD1. The second bindingdomain that binds to LYPD1 may, for example, comprise at least one, two,three, four, five, or six hypervariable regions (HVRs) selected from (a)HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3comprising the amino acid sequence of SEQ ID NO: 177; (d) HVR-L1comprising the amino acid sequence of SEQ ID NO: 178; (e) HVR-L2comprising the amino acid sequence of SEQ ID NO: 179; and (f) HVR-L3comprising the amino acid sequence of SEQ ID NO: 180, such as possessedby the anti-LYPD1 antibody, YWO.49.H6. In some instances, the secondbinding domain that binds to LYPD1 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 272; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 273; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 31; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 32; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 33; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:34; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 35; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 36, such asSP34v52, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 37; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 38; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 39; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:40; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 41; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 42, such as41D9a, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to FcRH5. Thesecond binding domain that binds to FcRH5 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to LYPD1. Thesecond binding domain that binds to LYPD1 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 43; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 44; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 45; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:46; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 47; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 48, such as13A3.v2, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 49; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 50; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 51; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:52; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 53; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 54, such as30A1, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to FcRH5. Thesecond binding domain that binds to FcRH5 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to LYPD1. Thesecond binding domain that binds to LYPD1 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 55; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 56; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 57; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:58; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 59; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 60, such as30A1.v2, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 61; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 62; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 63; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:64; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 65; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 66, such ash21A9, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 67; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 68; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 69; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:70; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 71; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 72, such as21B2, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 73; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 74; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 75; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:76; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 77; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 78, such as125A1, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 79; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 80; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 81; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:82; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 83; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 84, such as72H6, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 85; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 86; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 87; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:88; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 89; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 90, such as19B1, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to FcRH5. The secondbinding domain that binds to FcRH5 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to LYPD1. The secondbinding domain that binds to LYPD1 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to RET. The secondbinding domain that binds to RET may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 91; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 92; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 93; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:94; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 95; and(f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 96, such as71H7, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to CD20. Thesecond binding domain that binds to CD20 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to FcRH5. Thesecond binding domain that binds to FcRH5 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 163; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:164; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 165;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168, such aspossessed by the anti-FcRH5 antibody, 1G7. In some instances, the secondbinding domain that binds to FcRH5 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 268; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 269; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to HER2. Thesecond binding domain that binds to HER2 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to HER2. Thesecond binding domain that binds to HER2 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 581; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:582; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 583;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 584; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 585; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 586, such aspossessed by the anti-HER2 antibody, 2C4. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 593; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 594; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to HER2. Thesecond binding domain that binds to HER2 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to LYPD1. Thesecond binding domain that binds to LYPD1 may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180, such aspossessed by the anti-LYPD1 antibody, YWO.49.H6. In some instances, thesecond binding domain that binds to LYPD1 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 272;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 273;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to RET. Thesecond binding domain that binds to RET may, for example, comprise atleast one, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 613; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:614; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 615;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 616; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 617; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 618, such aspossessed by the anti-RET antibody, 41205.v6. In some instances, thesecond binding domain that binds to RET may, for example, comprise (a) aVH domain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 629; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 630; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 97; (b) HVR-H2 comprising the amino acid sequenceof SEQ ID NO: 98; (c) HVR-H3 comprising the amino acid sequence of SEQID NO: 99; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO:100; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 101;and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 102,such as 14C7, may have a second binding domain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 174, such as possessed by the anti-HER2 antibody,hu4D5. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 103; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 104; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 105; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 106; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 107; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 108, such as 127B3, may have a second bindingdomain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 174, such as possessed by the anti-HER2 antibody,hu4D5. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 109; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 110; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 111; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 112; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 113; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 114, such as 18F12, may have a second bindingdomain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 174, such as possessed by the anti-HER2 antibody,hu4D5. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 115; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 116; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 117; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 120, such as 27H5-1, may have a second bindingdomain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 174, such as possessed by the anti-HER2 antibody,hu4D5. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 121; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 122; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 123; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 124; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 125; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 126, such as 39B7, may have a second bindingdomain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 174, such as possessed by the anti-HER2 antibody,hu4D5. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 127; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 128; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 129; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 130; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 131; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 132, such as 40D2, may have a second bindingdomain that binds to TenB2.

In another instance, from (a) HVR-H1 comprising the amino acid sequenceof SEQ ID NO: 631; (b) HVR-H2 comprising the amino acid sequence of SEQID NO: 632; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:633; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 634;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 635; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 636, such as43H8, may have a second binding domain that binds to CD20. The secondbinding domain that binds to CD20 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 157; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:158; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 159;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 160; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162, such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900). In some instances, the second binding domain that binds toCD20 may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 266; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 267; or (c) a VH domain as in (a) and a VLdomain as in (b), such as possessed by the anti-CD20 antibody, 2H7.v16(described in U.S. Pat. No. 7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 174, such as possessed by the anti-HER2 antibody,hu4D5. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 631; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 632; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 633; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 634; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 635; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 636, such as 43H8, may have a second bindingdomain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected (a) HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ IDNO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as79B7, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected (a) HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 133; (b) HVR-H2 comprising the amino acid sequence of SEQ IDNO: 134; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:135; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 136;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 137; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 138, such as79B7, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 587; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:588; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 589;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 590; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 591; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 592, such aspossessed by the anti-HER2 antibody, 7C2. In some instances, the secondbinding domain that binds to HER2 may, for example, comprise (a) a VHdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 595; (b) a VLdomain comprising an amino acid sequence having at least 90% sequenceidentity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity) to, or the sequence of, SEQ ID NO: 596; or (c) a VHdomain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b) In some instances, an anti-CD3 antibody having a firstbinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 133; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 133; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 134; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 135; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 136; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 137; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 138, such as 79B7, may have a second bindingdomain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected (a) HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 139; (b) HVR-H2 comprising the amino acid sequence of SEQ IDNO: 140; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO:141; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142;(e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144, such as95A2, may have a second binding domain that binds to HER2. The secondbinding domain that binds to HER2 may, for example, comprise at leastone, two, three, four, five, or six hypervariable regions (HVRs)selected from (a) HVR-H1 comprising the amino acid sequence of SEQ IDNO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO:170; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171;(d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (e)HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (f)HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174, such aspossessed by the anti-HER2 antibody, hu4D5. In some instances, thesecond binding domain that binds to HER2 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 270;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 271;or (c) a VH domain as in (a) and a VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b) In some instances, an anti-CD3 antibody having a firstbinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 139; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 139; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 140; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 141; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 142; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 143; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 144, such as 95A2, may have a second bindingdomain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 174, such as possessed by the anti-HER2 antibody,hu4D5. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b) In some instances, an anti-CD3 antibody having a firstbinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 145; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 145; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 146; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 147; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 148; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 149; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 150, such as 118G9, may have a second bindingdomain that binds to TenB2.

In another instance, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to CD20. The second binding domain that binds to CD20may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 157; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 158; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 159; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 160; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 161; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 162, such as possessed by the anti-CD20 antibody,2H7.v16 (described in U.S. Pat. No. 7,799,900). In some instances, thesecond binding domain that binds to CD20 may, for example, comprise (a)a VH domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 266;(b) a VL domain comprising an amino acid sequence having at least 90%sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity) to, or the sequence of, SEQ ID NO: 267;or (c) a VH domain as in (a) and a VL domain as in (b), such aspossessed by the anti-CD20 antibody, 2H7.v16 (described in U.S. Pat. No.7,799,900).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to FcRH5. The second binding domain that binds toFcRH5 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 163; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 164; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 165; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 166; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 167; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 168, such as possessed by the anti-FcRH5antibody, 1G7. In some instances, the second binding domain that bindsto FcRH5 may, for example, comprise (a) a VH domain comprising an aminoacid sequence having at least 90% sequence identity (e.g., at least 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 268; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 269; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 170; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 171; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 172; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 173; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 174, such as possessed by the anti-HER2 antibody,hu4D5. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 271; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 581; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 582; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 583; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 584; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 585; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 586, such as possessed by the anti-HER2 antibody,2C4. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 593; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 594; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to HER2. The second binding domain that binds to HER2may, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 587; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 588; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 589; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 590; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 591; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 592, such as possessed by the anti-HER2 antibody,7C2. In some instances, the second binding domain that binds to HER2may, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 595; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 596; or (c) a VH domain as in (a) and a VLdomain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156 such as Rab17, may have a second bindingdomain that binds to LYPD1. The second binding domain that binds toLYPD1 may, for example, comprise at least one, two, three, four, five,or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprisingthe amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising theamino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the aminoacid sequence of SEQ ID NO: 177; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 178; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 179; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 180, such as possessed by the anti-LYPD1antibody, YWO.49.H6. In some instances, the second binding domain thatbinds to LYPD1 may, for example, comprise (a) a VH domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 272; (b) a VL domain comprising anamino acid sequence having at least 90% sequence identity (e.g., atleast 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity)to, or the sequence of, SEQ ID NO: 273; or (c) a VH domain as in (a) anda VL domain as in (b).

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to LY6G6D.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to PMEL17.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to LY6E.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to CD19.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to CD33.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to CD22.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to CD79A.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to CD79B.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to EDAR.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to GFRA1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to MRP4.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to RET. The second binding domain that binds to RETmay, for example, comprise at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 613; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 614; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 615; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 616; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 617; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 618, such as possessed by the anti-RET antibody,41205.v6. In some instances, the second binding domain that binds to RETmay, for example, comprise (a) a VH domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 629; (b) a VL domain comprising an amino acidsequence having at least 90% sequence identity (e.g., at least 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or thesequence of, SEQ ID NO: 630; or (c) a VH domain as in (a) and a VLdomain as in (b) In some instances, an anti-CD3 antibody having a firstbinding domain comprising at least one, two, three, four, five, or sixhypervariable regions (HVRs) selected from (a) HVR-H1 comprising theamino acid sequence of SEQ ID NO: 151; (b) HVR-H2 comprising the aminoacid sequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to Steap1.

In some instances, an anti-CD3 antibody having a first binding domaincomprising at least one, two, three, four, five, or six hypervariableregions (HVRs) selected from (a) HVR-H1 comprising the amino acidsequence of SEQ ID NO: 151; (b) HVR-H2 comprising the amino acidsequence of SEQ ID NO: 152; (c) HVR-H3 comprising the amino acidsequence of SEQ ID NO: 153; (d) HVR-L1 comprising the amino acidsequence of SEQ ID NO: 154; (e) HVR-L2 comprising the amino acidsequence of SEQ ID NO: 155; and (f) HVR-L3 comprising the amino acidsequence of SEQ ID NO: 156, such as Rab17, may have a second bindingdomain that binds to TenB2.

In some embodiments, bispecific antibodies may also be used to localizecytotoxic agents to cells which express a tumor antigen, such as a tumorantigen listed in Table 1 (e.g., CD20, FcRH5, HER2, LYPD1, LY6G6D,PMEL17, LY6E, CD19, CD33, CD22, CD79A, CD79B, EDAR, GFRA1, MRP4, RET,Steap1, or TenB2). Bispecific antibodies can also be prepared as fulllength antibodies or antibody fragments.

Techniques for making multispecific antibodies include, but are notlimited to, recombinant co-expression of two immunoglobulin heavychain-light chain pairs having different specificities (see Milstein andCuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al.,EMBO J. 10: 3655 (1991)), and “knob-in-hole” engineering (see, e.g.,U.S. Pat. No. 5,731,168). “Knob-in-hole” engineering of multispecificantibodies may be utilized to generate a first arm containing a knob anda second arm containing the hole into which the knob of the first armmay bind. The knob of the multispecific antibodies of the invention maybe an anti-CD3 arm in one embodiment. Alternatively, the knob of themultispecific antibodies of the invention may be an anti-target/antigenarm in one embodiment. The hole of the multispecific antibodies of theinvention may be an anti-CD3 arm in one embodiment. Alternatively, thehole of the multispecific antibodies of the invention may be ananti-target/antigen arm in one embodiment. Multispecific antibodies mayalso be engineered using immunoglobulin crossover (also known as Fabdomain exchange or CrossMab format) technology (see eg., WO2009/080253;Schaefer et al., Proc. Natl. Acad. Sci. USA, 108:11187-11192 (2011)).Multi-specific antibodies may also be made by engineering electrostaticsteering effects for making antibody Fc-heterodimeric molecules (WO2009/089004A1); cross-linking two or more antibodies or fragments (see,e.g., U.S. Pat. No. 4,676,980, and Brennan et al., Science, 229: 81(1985)); using leucine zippers to produce bi-specific antibodies (see,e.g., Kostelny et al., J. Immunol., 148(5):1547-1553 (1992)); using“diabody” technology for making bispecific antibody fragments (see,e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448(1993)); and using single-chain Fv (sFv) dimers (see, e.g. Gruber etal., J. Immunol., 152:5368 (1994)); and preparing trispecific antibodiesas described, e.g., in Tutt et al. J. Immunol. 147: 60 (1991).

Engineered antibodies with three or more functional antigen bindingsites, including “Octopus antibodies,” are also included herein (see,e.g. US 2006/0025576A1).

The antibodies, or antibody fragments thereof, may also include a “DualActing FAb” or “DAF” comprising an antigen binding site that binds toCD3 as well as another, different antigen (e.g., a second biologicalmolecule) (see, e.g., US 2008/0069820).

7. Antibody Variants

In certain embodiments, amino acid sequence variants of the anti-CD3antibodies of the invention (e.g., bispecific anti-CD3 antibodies of theinvention that bind to CD3 and a second biological molecule, e.g., acell surface antigen, e.g., a tumor antigen, such as TDB antibodies ofthe invention or variants thereof) are contemplated. For example, it maybe desirable to improve the binding affinity and/or other biologicalproperties of the antibody. Amino acid sequence variants of an antibodymay be prepared by introducing appropriate modifications into thenucleotide sequence encoding the antibody, or by peptide synthesis. Suchmodifications include, for example, deletions from, and/or insertionsinto and/or substitutions of residues within the amino acid sequences ofthe antibody. Any combination of deletion, insertion, and substitutioncan be made to arrive at the final construct, provided that the finalconstruct possesses the desired characteristics, for example,antigen-binding.

a. Substitution, Insertion, and Deletion Variants

In certain embodiments, antibody variants having one or more amino acidsubstitutions are provided. Sites of interest for substitutionalmutagenesis include the HVRs and FRs. Conservative substitutions areshown in Table 2 under the heading of “preferred substitutions.” Moresubstantial changes are provided in Table 2 under the heading of“exemplary substitutions,” and as further described below in referenceto amino acid side chain classes. Amino acid substitutions may beintroduced into an antibody of interest and the products screened for adesired activity, for example, retained/improved antigen binding,decreased immunogenicity, or improved ADCC or CDC.

TABLE 2 Exemplary and Preferred Amino Acid Substitutions OriginalExemplary Preferred Residue Substitutions Substitutions Ala (A) Val;Leu; Ile Val Arg (R) Lys; Gln; Asn Lys Asn (N) Gln; His; Asp, Lys; ArgGln Asp (D) Glu; Asn Glu Cys (C) Ser; Ala Ser Gln (Q) Asn; Glu Asn Glu(E) Asp; Gln Asp Gly (G) Ala Ala His (H) Asn; Gln; Lys; Arg Arg Ile (I)Leu; Val; Met; Ala; Phe; Norleucine Leu Leu (L) Norleucine; Ile; Val;Met; Ala; Phe Ile Lys (K) Arg; Gln; Asn Arg Met (M) Leu; Phe; Ile LeuPhe (F) Trp; Leu; Val; Ile; Ala; Tyr Tyr Pro (P) Ala Ala Ser (S) Thr ThrThr (T) Val; Ser Ser Trp (W) Tyr; Phe Tyr Tyr (Y) Trp; Phe; Thr; Ser PheVal (V) Ile; Leu; Met; Phe; Ala; Norleucine LeuAmino acids may be grouped according to common side-chain properties:

(1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;

(2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;

(3) acidic: Asp, Glu;

(4) basic: His, Lys, Arg;

(5) residues that influence chain orientation: Gly, Pro;

(6) aromatic: Trp, Tyr, Phe.

Non-conservative substitutions will entail exchanging a member of one ofthese classes for another class.

One type of substitutional variant involves substituting one or morehypervariable region residues of a parent antibody (e.g. a humanized orhuman antibody). Generally, the resulting variant(s) selected forfurther study will have modifications (e.g., improvements) in certainbiological properties (e.g., increased affinity, reduced immunogenicity)relative to the parent antibody and/or will have substantially retainedcertain biological properties of the parent antibody. An exemplarysubstitutional variant is an affinity matured antibody, which may beconveniently generated, e.g., using phage display-based affinitymaturation techniques such as those described herein. Briefly, one ormore HVR residues are mutated and the variant antibodies displayed onphage and screened for a particular biological activity (e.g. bindingaffinity).

Alterations (e.g., substitutions) may be made in HVRs, e.g., to improveantibody affinity. Such alterations may be made in HVR “hotspots,” i.e.,residues encoded by codons that undergo mutation at high frequencyduring the somatic maturation process (see, e.g., Chowdhury, MethodsMol. Biol. 207:179-196 (2008)), and/or residues that contact antigen,with the resulting variant VH or VL being tested for binding affinity.Affinity maturation by constructing and reselecting from secondarylibraries has been described, e.g., in Hoogenboom et al. in Methods inMolecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa,N.J., (2001).) In some embodiments of affinity maturation, diversity isintroduced into the variable genes chosen for maturation by any of avariety of methods (e.g., error-prone PCR, chain shuffling, oroligonucleotide-directed mutagenesis). A secondary library is thencreated. The library is then screened to identify any antibody variantswith the desired affinity. Another method to introduce diversityinvolves HVR-directed approaches, in which several HVR residues (e.g.,4-6 residues at a time) are randomized. HVR residues involved in antigenbinding may be specifically identified, e.g., using alanine scanningmutagenesis or modeling. CDR-H3 and CDR-L3 in particular are oftentargeted.

In certain embodiments, substitutions, insertions, or deletions mayoccur within one or more HVRs so long as such alterations do notsubstantially reduce the ability of the antibody to bind antigen. Forexample, conservative alterations (e.g., conservative substitutions asprovided herein) that do not substantially reduce binding affinity maybe made in HVRs. Such alterations may, for example, be outside ofantigen contacting residues in the HVRs. In certain embodiments of thevariant VH and VL sequences provided above, each HVR either isunaltered, or contains no more than one, two or three amino acidsubstitutions.

A useful method for identification of residues or regions of an antibodythat may be targeted for mutagenesis is called “alanine scanningmutagenesis” as described by Cunningham and Wells (1989) Science,244:1081-1085. In this method, a residue or group of target residues(e.g., charged residues such as arg, asp, his, lys, and glu) areidentified and replaced by a neutral or negatively charged amino acid(e.g., alanine or polyalanine) to determine whether the interaction ofthe antibody with antigen is affected. Further substitutions may beintroduced at the amino acid locations demonstrating functionalsensitivity to the initial substitutions. Alternatively, oradditionally, a crystal structure of an antigen-antibody complex toidentify contact points between the antibody and antigen. Such contactresidues and neighboring residues may be targeted or eliminated ascandidates for substitution. Variants may be screened to determinewhether they contain the desired properties.

Amino acid sequence insertions include amino- and/or carboxyl-terminalfusions ranging in length from one residue to polypeptides containing ahundred or more residues, as well as intrasequence insertions of singleor multiple amino acid residues. Examples of terminal insertions includean antibody with an N-terminal methionyl residue. Other insertionalvariants of the antibody molecule include the fusion to the N- orC-terminus of the antibody to an enzyme (e.g. for ADEPT) or apolypeptide which increases the serum half-life of the antibody.

b. Glycosylation Variants

In certain embodiments, anti-CD3 antibodies of the invention (e.g.,bispecific anti-CD3 antibodies of the invention that bind to CD3 and asecond biological molecule, e.g., a cell surface antigen, e.g., a tumorantigen, such as TDB antibodies of the invention or variants thereof)can be altered to increase or decrease the extent to which the antibodyis glycosylated. Addition or deletion of glycosylation sites to anti-CD3antibody of the invention may be conveniently accomplished by alteringthe amino acid sequence such that one or more glycosylation sites iscreated or removed.

Where the antibody comprises an Fc region, the carbohydrate attachedthereto may be altered. Native antibodies produced by mammalian cellstypically comprise a branched, biantennary oligosaccharide that isgenerally attached by an N-linkage to Asn297 of the CH2 domain of the Fcregion. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). Theoligosaccharide may include various carbohydrates, e.g., mannose,N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as afucose attached to a GlcNAc in the “stem” of the biantennaryoligosaccharide structure. In some embodiments, modifications of theoligosaccharide in an antibody of the invention may be made in order tocreate antibody variants with certain improved properties.

In one embodiment, anti-CD3 antibody variants are provided having acarbohydrate structure that lacks fucose attached (directly orindirectly) to an Fc region. For example, the amount of fucose in suchantibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from20% to 40%. The amount of fucose is determined by calculating theaverage amount of fucose within the sugar chain at Asn297, relative tothe sum of all glycostructures attached to Asn 297 (e. g. complex,hybrid and high mannose structures) as measured by MALDI-TOF massspectrometry, as described in WO 2008/077546, for example. Asn297 refersto the asparagine residue located at about position 297 in the Fc region(EU numbering of Fc region residues); however, Asn297 may also belocated about ±3 amino acids upstream or downstream of position 297,i.e., between positions 294 and 300, due to minor sequence variations inantibodies. Such fucosylation variants may have improved ADCC function.See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publicationsrelated to “defucosylated” or “fucose-deficient” antibody variantsinclude: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614;US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki etal. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech.Bioeng. 87: 614 (2004). Examples of cell lines capable of producingdefucosylated antibodies include Lec13 CHO cells deficient in proteinfucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986);US Pat Appl No US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1,Adams et al., especially at Example 11), and knockout cell lines, suchas alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see,e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. etal., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003/085107).

Anti-CD3 antibodies variants are further provided with bisectedoligosaccharides, for example, in which a biantennary oligosaccharideattached to the Fc region of the antibody is bisected by GlcNAc. Suchantibody variants may have reduced fucosylation and/or improved ADCCfunction. Examples of such antibody variants are described, e.g., in WO2003/011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana etal.); and US 2005/0123546 (Umana et al.). Antibody variants with atleast one galactose residue in the oligosaccharide attached to the Fcregion are also provided. Such antibody variants may have improved CDCfunction. Such antibody variants are described, e.g., in WO 1997/30087(Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

c. Fc Region Variants

In certain embodiments, one or more amino acid modifications may beintroduced into the Fc region of an anti-CD3 antibody of the invention(e.g., a bispecific anti-CD3 antibody of the invention that binds to CD3and a second biological molecule, e.g., a cell surface antigen, e.g., atumor antigen, such as a TDB antibody of the invention or variantthereof), thereby generating an Fc region variant (see e.g., US2012/0251531). The Fc region variant may comprise a human Fc regionsequence (e.g., a human IgG1, IgG2, IgG3 or IgG4 Fc region) comprisingan amino acid modification (e.g., a substitution) at one or more aminoacid positions.

In certain embodiments, the invention contemplates an anti-CD3 antibodyvariant that possesses some but not all effector functions, which makeit a desirable candidate for applications in which the half life of theantibody in vivo is important yet certain effector functions (such ascomplement and ADCC) are unnecessary or deleterious. In vitro and/or invivo cytotoxicity assays can be conducted to confirm thereduction/depletion of CDC and/or ADCC activities. For example, Fcreceptor (FcR) binding assays can be conducted to ensure that theantibody lacks FcγR binding (hence likely lacking ADCC activity), butretains FcRn binding ability. The primary cells for mediating ADCC, NKcells, express Fc(RIII only, whereas monocytes express Fc(RI, Fc(RII andFc(RIII. FcR expression on hematopoietic cells is summarized in Table 3on page 464 of Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991).Non-limiting examples of in vitro assays to assess ADCC activity of amolecule of interest is described in U.S. Pat. No. 5,500,362 (see, e.g.Hellstrom, I. et al. Proc. Nat'l Acad. Sci. USA 83:7059-7063 (1986)) andHellstrom, I et al., Proc. Nat'l Acad. Sci. USA 82:1499-1502 (1985);U.S. Pat. No. 5,821,337 (see Bruggemann, M. et al., J. Exp. Med.166:1351-1361 (1987)). Alternatively, non-radioactive assays methods maybe employed (see, for example, ACTI™ non-radioactive cytotoxicity assayfor flow cytometry (CellTechnology, Inc. Mountain View, Calif.; andCytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, Wis.).Useful effector cells for such assays include peripheral bloodmononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively,or additionally, ADCC activity of the molecule of interest may beassessed in vivo, e.g., in a animal model such as that disclosed inClynes et al. Proc. Nat'l Acad. Sci. USA 95:652-656 (1998). C1q bindingassays may also be carried out to confirm that the antibody is unable tobind C1q and hence lacks CDC activity. See, e.g., C1q and C3c bindingELISA in WO 2006/029879 and WO 2005/100402. To assess complementactivation, a CDC assay may be performed (see, for example,Gazzano-Santoro et al. J. Immunol. Methods 202:163 (1996); Cragg, M. S.et al. Blood. 101:1045-1052 (2003); and Cragg, M. S. and M. J. GlennieBlood. 103:2738-2743 (2004)). FcRn binding and in vivo clearance/halflife determinations can also be performed using methods known in the art(see, e.g., Petkova, S. B. et al. Int'l. Immunol. 18(12):1759-1769(2006)).

Antibodies with reduced effector function include those withsubstitution of one or more of Fc region residues 238, 265, 269, 270,297, 327 and 329 (U.S. Pat. Nos. 6,737,056 and 8,219,149). Such Fcmutants include Fc mutants with substitutions at two or more of aminoacid positions 265, 269, 270, 297 and 327, including the so-called“DANA” Fc mutant with substitution of residues 265 and 297 to alanine(U.S. Pat. Nos. 7,332,581 and 8,219,149).

In certain embodiments, the proline at position 329 of a wild-type humanFc region in the antibody is substituted with glycine or arginine or anamino acid residue large enough to destroy the proline sandwich withinthe Fc/Fc.gamma. receptor interface that is formed between the proline329 of the Fc and tryptophan residues Trp 87 and Trp 110 of FcgRIII(Sondermann et al.: Nature 406, 267-273 (20 Jul. 2000)). In certainembodiments, the antibody comprises at least one further amino acidsubstitution. In one embodiment, the further amino acid substitution isS228P, E233P, L234A, L235A, L235E, N297A, N297D, or P331S, and still inanother embodiment the at least one further amino acid substitution isL234A and L235A of the human IgG1 Fc region or S228P and L235E of thehuman IgG4 Fc region (see e.g., US 2012/0251531), and still in anotherembodiment the at least one further amino acid substitution is L234A andL235A and P329G of the human IgG1 Fc region.

Certain antibody variants with improved or diminished binding to FcRsare described. (See, e.g., U.S. Pat. No. 6,737,056; WO 2004/056312, andShields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).) In certainembodiments, an antibody variant comprises an Fc region with one or moreamino acid substitutions which improve ADCC, e.g., substitutions atpositions 298, 333, and/or 334 of the Fc region (EU numbering ofresidues).

In some embodiments, alterations are made in the Fc region that resultin altered (i.e., either improved or diminished) C1q binding and/orComplement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat.No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164:4178-4184 (2000).

Antibodies with increased half lives and improved binding to theneonatal Fc receptor (FcRn), which is responsible for the transfer ofmaternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) andKim et al., J. Immunol. 24:249 (1994)), are described inUS2005/0014934A1 (Hinton et al.). Those antibodies comprise an Fc regionwith one or more substitutions therein which improve binding of the Fcregion to FcRn. Such Fc variants include those with substitutions at oneor more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307,311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434,e.g., substitution of Fc region residue 434 (U.S. Pat. No. 7,371,826).

See also Duncan & Winter, Nature 322:738-40 (1988); U.S. Pat. Nos.5,648,260; 5,624,821; and WO 94/29351 concerning other examples of Fcregion variants.

In some aspects the anti-CD3 antibody (e.g., bispecific anti-CD3antibody) comprises an Fc region comprising an N297G mutation. In someembodiments, the anti-CD3 antibody comprising the N297G mutationcomprises an anti-CD3 arm comprising a first binding domain comprisingthe following six HVRs: (a) an HVR-H1 comprising the amino acid sequenceof SEQ ID NO: 1; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 2; (c) an HVR-H3 comprising the amino acid sequence of SEQ ID NO:3; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e)an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) anHVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and ananti-CD20 arm comprising a second binding domain comprising thefollowing six HVRs: (a) an HVR-H1 comprising the amino acid sequence ofSEQ ID NO: 157; (b) an HVR-H2 comprising the amino acid sequence of SEQID NO: 158; (c) an HVR-H3 comprising the amino acid sequence of SEQ IDNO: 159; (d) an HVR-L1 comprising the amino acid sequence of SEQ ID NO:160; (e) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 161;and (f) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 162.

In some embodiments, the anti-CD3 antibody comprising the N297G mutationcomprises an anti-CD3 arm comprising a first binding domain comprising(a) a VH domain comprising an amino acid sequence of SEQ ID NO: 184 and(b) a VL domain comprising an amino acid sequence of SEQ ID NO: 185, andan anti-CD20 arm comprising a second binding domain comprising (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 266 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 267.

In some embodiments, the anti-CD3 antibody comprising the N297G mutationcomprises one or more heavy chain constant domains, wherein the one ormore heavy chain constant domains are selected from a first CH1 (CH1₁)domain, a first CH2 (CH2₁) domain, a first CH3 (CH3₁) domain, a secondCH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂)domain. In some instances, at least one of the one or more heavy chainconstant domains is paired with another heavy chain constant domain. Insome instances, the CH3₁ and CH3₂ domains each comprise a protuberanceor cavity, and wherein the protuberance or cavity in the CH3₁ domain ispositionable in the cavity or protuberance, respectively, in the CH3₂domain. In some instances, the CH3₁ and CH3₂ domains meet at aninterface between said protuberance and cavity. In some instances, theCH2₁ and CH2₂ domains each comprise a protuberance or cavity, andwherein the protuberance or cavity in the CH2₁ domain is positionable inthe cavity or protuberance, respectively, in the CH2₂ domain. In otherinstances, the CH2₁ and CH2₂ domains meet at an interface between saidprotuberance and cavity. In some instances, the anti-CD3 antibody is anIgG1 antibody.

In other embodiments, the anti-CD3 antibody comprising the N297Gmutation comprises an anti-CD3 arm comprising a first binding domaincomprising (a) a VH domain comprising an amino acid sequence of SEQ IDNO: 184 and (b) a VL domain comprising an amino acid sequence of SEQ IDNO: 185, and an anti-CD20 arm comprising a second binding domaincomprising (a) a VH domain comprising an amino acid sequence of SEQ IDNO: 266 and (b) a VL domain comprising an amino acid sequence of SEQ IDNO: 267, wherein (a) the anti-CD3 arm comprises T366S, L368A, Y407V, andN297G substitution mutations and (b) the anti-CD20 arm comprises T366Wand N297G substitution mutations.

d. Cysteine Engineered Antibody Variants

In certain embodiments, it may be desirable to create cysteineengineered antibodies, e.g., “thioMAbs,” in which one or more residuesof an antibody are substituted with cysteine residues. In particularembodiments, the substituted residues occur at accessible sites of theantibody. By substituting those residues with cysteine, reactive thiolgroups are thereby positioned at accessible sites of the antibody andmay be used to conjugate the antibody to other moieties, such as drugmoieties or linker-drug moieties, to create an immunoconjugate, asdescribed further herein. In certain embodiments, any one or more of thefollowing residues may be substituted with cysteine: V205 (Kabatnumbering) of the light chain; A118 (EU numbering) of the heavy chain;and S400 (EU numbering) of the heavy chain Fc region. Cysteineengineered antibodies may be generated as described, for example, inU.S. Pat. No. 7,521,541.

e. Antibody Derivatives

In certain embodiments, an anti-CD3 antibody of the invention (e.g.,bispecific anti-CD3 antibody of the invention that binds to CD3 and asecond biological molecule, e.g., a cell surface antigen, e.g., a tumorantigen, such as a TDB antibody of the invention or variant thereof)provided herein may be further modified to contain additionalnonproteinaceous moieties that are known in the art and readilyavailable. The moieties suitable for derivatization of the antibodyinclude but are not limited to water soluble polymers. Non-limitingexamples of water soluble polymers include, but are not limited to,polyethylene glycol (PEG), copolymers of ethylene glycol/propyleneglycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1,3,6-trioxane, ethylene/maleicanhydride copolymer, polyaminoacids (either homopolymers or randomcopolymers), and dextran or poly(n-vinyl pyrrolidone)polyethyleneglycol, propropylene glycol homopolymers, prolypropylene oxide/ethyleneoxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinylalcohol, and mixtures thereof. Polyethylene glycol propionaldehyde mayhave advantages in manufacturing due to its stability in water. Thepolymer may be of any molecular weight, and may be branched orunbranched. The number of polymers attached to the antibody may vary,and if more than one polymer are attached, they can be the same ordifferent molecules. In general, the number and/or type of polymers usedfor derivatization can be determined based on considerations including,but not limited to, the particular properties or functions of theantibody to be improved, whether the antibody derivative will be used ina therapy under defined conditions, etc.

In another embodiment, conjugates of an antibody and nonproteinaceousmoiety that may be selectively heated by exposure to radiation areprovided. In one embodiment, the nonproteinaceous moiety is a carbonnanotube (Kam et al., Proc. Natl. Acad. Sci. USA 102: 11600-11605(2005)). The radiation may be of any wavelength, and includes, but isnot limited to, wavelengths that do not harm ordinary cells, but whichheat the nonproteinaceous moiety to a temperature at which cellsproximal to the antibody-nonproteinaceous moiety are killed.

B. Recombinant Methods and Compositions

Anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3antibodies of the invention that bind to CD3 and a second biologicalmolecule, e.g., a cell surface antigen, e.g., a tumor antigen, such asTDB antibodies of the invention or variants thereof) may be producedusing recombinant methods and compositions, for example, as described inU.S. Pat. No. 4,816,567. In one embodiment, isolated nucleic acidencoding an anti-CD3 antibody described herein is provided. Such nucleicacid may encode an amino acid sequence comprising the VL and/or an aminoacid sequence comprising the VH of the antibody (e.g., the light and/orheavy chains of the antibody). In a further embodiment, one or morevectors (e.g., expression vectors) comprising such nucleic acid areprovided. In a further embodiment, a host cell comprising such nucleicacid is provided. In one such embodiment, a host cell comprises (e.g.,has been transformed with): (1) a vector comprising a nucleic acid thatencodes an amino acid sequence comprising the VL of the antibody and anamino acid sequence comprising the VH of the antibody, or (2) a firstvector comprising a nucleic acid that encodes an amino acid sequencecomprising the VL of the antibody and a second vector comprising anucleic acid that encodes an amino acid sequence comprising the VH ofthe antibody. In one embodiment, the host cell is eukaryotic, e.g. aChinese Hamster Ovary (CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp20cell). In one embodiment, a method of making an anti-CD3 antibody isprovided, wherein the method comprises culturing a host cell comprisinga nucleic acid encoding the antibody, as provided above, underconditions suitable for expression of the antibody, and optionallyrecovering the antibody from the host cell (or host cell culturemedium).

For recombinant production of an anti-CD3 antibody, nucleic acidencoding an antibody, e.g., as described above, is isolated and insertedinto one or more vectors for further cloning and/or expression in a hostcell. Such nucleic acid may be readily isolated and sequenced usingconventional procedures (e.g., by using oligonucleotide probes that arecapable of binding specifically to genes encoding the heavy and lightchains of the antibody).

Suitable host cells for cloning or expression of antibody-encodingvectors include prokaryotic or eukaryotic cells described herein. Forexample, antibodies may be produced in bacteria, in particular whenglycosylation and Fc effector function are not needed. For expression ofantibody fragments and polypeptides in bacteria, see, e.g., U.S. Pat.Nos. 5,648,237, 5,789,199, and 5,840,523. (See also Charlton, Methods inMolecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa,N.J., 2003), pp. 245-254, describing expression of antibody fragments inE. coli.) After expression, the antibody may be isolated from thebacterial cell paste in a soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microbes such as filamentousfungi or yeast are suitable cloning or expression hosts forantibody-encoding vectors, including fungi and yeast strains whoseglycosylation pathways have been “humanized,” resulting in theproduction of an antibody with a partially or fully human glycosylationpattern. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li etal., Nat. Biotech. 24:210-215 (2006).

Suitable host cells for the expression of glycosylated antibody are alsoderived from multicellular organisms (invertebrates and vertebrates).Examples of invertebrate cells include plant and insect cells.

Numerous baculoviral strains have been identified which may be used inconjunction with insect cells, particularly for transfection ofSpodoptera frugiperda cells.

Plant cell cultures can also be utilized as hosts. See, e.g., U.S. Pat.Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429(describing PLANTIBODIES™ technology for producing antibodies intransgenic plants).

Vertebrate cells may also be used as hosts. For example, mammalian celllines that are adapted to grow in suspension may be useful. Otherexamples of useful mammalian host cell lines are monkey kidney CV1 linetransformed by SV40 (COS-7); human embryonic kidney line (293 or 293cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977));baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells asdescribed, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkeykidney cells (CV1); African green monkey kidney cells (VERO-76); humancervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo ratliver cells (BRL 3A); human lung cells (W138); human liver cells (HepG2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., inMather et al., Annals N.Y. Acad. Sci. 383:44-68 (1982); MRC 5 cells; andFS4 cells. Other useful mammalian host cell lines include Chinesehamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al.,Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines suchas Y0, NS0 and Sp2/0. For a review of certain mammalian host cell linessuitable for antibody production, see, e.g., Yazaki and Wu, Methods inMolecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa,N.J.), pp. 255-268 (2003).

C. Assays

Anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3antibodies of the invention that bind to CD3 and a second biologicalmolecule, e.g., a cell surface antigen, e.g., a tumor antigen, such asTDB antibodies of the invention or variants thereof) provided herein maybe identified, screened for, or characterized for theirphysical/chemical properties and/or biological activities by variousassays known in the art.

1. Binding Assays and Other Assays

In one aspect, an anti-CD3 antibody of the invention is tested for itsantigen binding activity, for example, by known methods such as ELISA,Western blot, etc.

In another aspect, competition assays may be used to identify anantibody that competes with an anti-CD3 antibody of the invention forbinding to CD3.

In an exemplary competition assay, immobilized CD3 is incubated in asolution comprising a first labeled antibody that binds to CD3 and asecond unlabeled antibody that is being tested for its ability tocompete with the first antibody for binding to CD3. The second antibodymay be present in a hybridoma supernatant. As a control, immobilized CD3is incubated in a solution comprising the first labeled antibody but notthe second unlabeled antibody. After incubation under conditionspermissive for binding of the first antibody to CD3, excess unboundantibody is removed, and the amount of label associated with immobilizedCD3 is measured. If the amount of label associated with immobilized CD3is substantially reduced in the test sample relative to the controlsample, then that indicates that the second antibody is competing withthe first antibody for binding to CD3. See, e.g., Harlow and Lane (1988)Antibodies: A Laboratory Manual. Ch. 14 (Cold Spring Harbor Laboratory,Cold Spring Harbor, N.Y.).

2. Activity Assays

In one aspect, assays are provided for identifying anti-CD3 antibodiesthereof having biological activity. Biological activity may include, forexample, binding to CD3 (e.g., CD3 on the surface of a T cell), or apeptide fragment thereof, either in vivo, in vitro, or ex vivo. In thecase of a multispecific (e.g., bispecific) anti-CD3 antibody of theinvention (e.g., a TDB antibody having one anti-CD3 arm and one arm thatrecognizes a second biological molecule, e.g., a cell surface antigen,e.g., a tumor antigen), biological activity may also include, forexample, effector cell activation (e.g., T cell (e.g., CD8+ and/or CD4+T cell) activation), effector cell population expansion (i.e., anincrease in T cell count), target cell population reduction (i.e., adecrease in the population of cells expressing the second biologicalmolecule on their cell surfaces), and/or target cell killing. Antibodieshaving such biological activity in vivo and/or in vitro are provided. Incertain embodiments, an antibody of the invention is tested for suchbiological activity, as described in detail in the Examples hereinbelow.

In some embodiments, the activity comprises ability to support B cellkilling and/or the activation of the cytotoxic T cells. In certainembodiments, an anti-B cell targeting anti-CD3 antibody of the invention(such as an anti-CD20 TDB) is tested for such B cell killing and/or theactivation of the cytotoxic effect of T cells biological activity by anyof the methods described herein, in particular the Examples. In someembodiments of any of these activity assays, PBMCs may be isolated fromwhole blood of healthy donors by Ficoll separation. In particular, humanblood may be collected in heparinized syringes, and PBMCs isolated usingLeucosep and Ficoll Paque Plus. If needed CD4+ T and CD8+ T cells may beseparated with Miltenyi kits according to manufacturer's instructions.

Further, cells may be washed in RPMI medium containing 10% FBS,supplemented with GlutaMax, penicillin & streptomycin, and ˜0.2 millionsuspended cells added to a 96-well U-bottom plate. Cells may be culturedin RPMI1640 supplemented with 10% FBS at 37° C. in a humidified standardcell culture incubator. For BJAB cell killing assays, 20,000 BJAB cellsmay be incubated with effector cells, either as huPBMCs or purified Tcells, as indicated ratios per assay, in the presence of variousconcentrations of TDB antibodies for 24 hours. For endogenous B cellkilling assays, 200,000 huPBMCs may be incubated with variousconcentrations of TDB antibodies for 24 hours.

After culturing, cells may be washed with FACS buffer (0.5% BSA, 0.05%Na Azide in PBS). Cells may then be stained in FACS buffer, washed withFACS buffer and suspended in 1001 μl of FACS buffer containing 1 μg/mlPropidium Iodide. Data may be collected on a FACSCalibur flow cytometerand analyzed using FlowJo. Live B cells may be gated out as PI-CD19+ orPI-CD20+ B cells by FACS, and absolute cell count may be obtained withFITC beads added to reaction mix as an internal counting control. Thepercent (%) of cell killing may be calculated based on non-TDB treatedcontrols. Activated T cells may be detected by CD69 and CD25 surfaceexpression using anti-CD69-FITC and anti-CD25-PE.

D. Immunoconjugates

The invention also provides immunoconjugates comprising an anti-CD3antibody herein conjugated to one or more cytotoxic agents, such aschemotherapeutic agents or drugs, growth inhibitory agents, toxins(e.g., protein toxins, enzymatically active toxins of bacterial, fungal,plant, or animal origin, or fragments thereof), or radioactive isotopes.

In one embodiment, an immunoconjugate is an antibody-drug conjugate(ADC) in which an antibody is conjugated to one or more drugs, includingbut not limited to a maytansinoid (see U.S. Pat. Nos. 5,208,020,5,416,064 and European Patent EP 0 425 235B1); an auristatin such asmonomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S.Pat. Nos. 5,635,483 and 5,780,588, and 7,498,298); a dolastatin; acalicheamicin or derivative thereof (see U.S. Pat. Nos. 5,712,374,5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode etal., Cancer Res. 58:2925-2928 (1998)); an anthracycline such asdaunomycin or doxorubicin (see Kratz et al., Current Med. Chem.13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagyet al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al.,Bioorg. & Med. Chem. Letters 12:1529-1532 (2002); King et al., J. Med.Chem. 45:4336-4343 (2002); and U.S. Pat. No. 6,630,579); methotrexate;vindesine; a taxane such as docetaxel, paclitaxel, larotaxel, tesetaxel,and ortataxel; a trichothecene; and CC1065.

In another embodiment, an immunoconjugate comprises an anti-CD3 antibodyas described herein conjugated to an enzymatically active toxin orfragment thereof, including but not limited to diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), Momordica charantiainhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

In another embodiment, an immunoconjugate comprises an anti-CD3 antibodyas described herein conjugated to a radioactive atom to form aradioconjugate. A variety of radioactive isotopes are available for theproduction of radioconjugates. Examples include At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰,Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu.When the radioconjugate is used for detection, it may comprise aradioactive atom for scintigraphic studies, for example tc99m or I123,or a spin label for nuclear magnetic resonance (NMR) imaging (also knownas magnetic resonance imaging, mri), such as iodine-123 again,iodine-131, indium-111, fluorine-19, carbon-13, nitrogen-15, oxygen-17,gadolinium, manganese or iron.

Conjugates of an antibody and cytotoxic agent may be made using avariety of bifunctional protein coupling agents such asN-succinimidyl-3-(2-pyridyldithio) propionate (SPDP),succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC),iminothiolane (IT), bifunctional derivatives of imidoesters (such asdimethyl adipimidate HCl), active esters (such as disuccinimidylsuberate), aldehydes (such as glutaraldehyde), bis-azido compounds (suchas bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (suchas bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astoluene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science 238:1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94/11026. Thelinker may be a “cleavable linker” facilitating release of a cytotoxicdrug in the cell. For example, an acid-labile linker,peptidase-sensitive linker, photolabile linker, dimethyl linker ordisulfide-containing linker (Chari et al., Cancer Res. 52:127-131(1992); U.S. Pat. No. 5,208,020) may be used.

The immunoconjugates or ADCs herein expressly contemplate, but are notlimited to such conjugates prepared with cross-linker reagentsincluding, but not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS,MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, sulfo-EMCS, sulfo-GMBS,sulfo-KMUS, sulfo-MBS, sulfo-SIAB, sulfo-SMCC, and sulfo-SMPB, and SVSB(succinimidyl-(4-vinylsulfone)benzoate) which are commercially available(e.g., from Pierce Biotechnology, Inc., Rockford, Ill., U.S.A).

E. Methods and Compositions for Diagnostics and Detection

In certain embodiments, any of the anti-CD3 antibodies of the invention(e.g., bispecific anti-CD3 antibodies of the invention that bind to CD3and a second biological molecule, e.g., a cell surface antigen, e.g., atumor antigen, such as TDB antibodies of the invention or variantsthereof) is useful for detecting the presence of CD3 in a biologicalsample. The term “detecting” as used herein encompasses quantitative orqualitative detection. In certain embodiments, a biological samplecomprises a cell or tissue.

In one embodiment, an anti-CD3 antibody for use in a method of diagnosisor detection is provided. In a further aspect, a method of detecting thepresence of CD3 in a biological sample is provided. In certainembodiments, the method comprises contacting the biological sample withan anti-CD3 antibody as described herein under conditions permissive forbinding of the anti-CD3 antibody to CD3, and detecting whether a complexis formed between the anti-CD3 antibody and CD3. Such method may be anin vitro or in vivo method.

In certain embodiments, labeled anti-CD3 antibodies are provided. Labelsinclude, but are not limited to, labels or moieties that are detecteddirectly (such as fluorescent, chromophoric, electron-dense,chemiluminescent, and radioactive labels), as well as moieties, such asenzymes or ligands, that are detected indirectly, e.g., through anenzymatic reaction or molecular interaction. Exemplary labels include,but are not limited to, the radioisotopes ³²P, ¹⁴O, ¹²⁵I, ³H, and ¹³¹I,fluorophores such as rare earth chelates or fluorescein and itsderivatives, rhodamine and its derivatives, dansyl, umbelliferone,luceriferases, e.g., firefly luciferase and bacterial luciferase (U.S.Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones,horseradish peroxidase (HRP), alkaline phosphatase, 3-galactosidase,glucoamylase, lysozyme, saccharide oxidases, e.g., glucose oxidase,galactose oxidase, and glucose-6-phosphate dehydrogenase, heterocyclicoxidases such as uricase and xanthine oxidase, coupled with an enzymethat employs hydrogen peroxide to oxidize a dye precursor such as HRP,lactoperoxidase, or microperoxidase, biotin/avidin, spin labels,bacteriophage labels, stable free radicals, and the like.

F. Pharmaceutical Formulations

Pharmaceutical formulations of an anti-CD3 antibody of the invention(e.g., bispecific anti-CD3 antibody of the invention that binds to CD3and a second biological molecule, e.g., a cell surface antigen, e.g., atumor antigen, such as a TDB antibody of the invention or variantthereof) are prepared by mixing such antibody having the desired degreeof purity with one or more optional pharmaceutically acceptable carriers(Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)),in the form of lyophilized formulations or aqueous solutions.Pharmaceutically acceptable carriers are generally nontoxic torecipients at the dosages and concentrations employed, and include, butare not limited to: buffers such as phosphate, citrate, and otherorganic acids; antioxidants including ascorbic acid and methionine;preservatives (such as octadecyldimethylbenzyl ammonium chloride;hexamethonium chloride; benzalkonium chloride; benzethonium chloride;phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol);low molecular weight (less than about 10 residues) polypeptides;proteins, such as serum albumin, gelatin, or immunoglobulins;hydrophilic polymers such as polyvinylpyrrolidone; amino acids such asglycine, glutamine, asparagine, histidine, arginine, or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugarssuch as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g. Zn-proteincomplexes); and/or non-ionic surfactants such as polyethylene glycol(PEG). Exemplary pharmaceutically acceptable carriers herein furtherinclude insterstitial drug dispersion agents such as solubleneutral-active hyaluronidase glycoproteins (sHASEGP), for example, humansoluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®,Baxter International, Inc.). Certain exemplary sHASEGPs and methods ofuse, including rHuPH20, are described in US Patent Publication Nos.2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined withone or more additional glycosaminoglycanases such as chondroitinases.

Exemplary lyophilized antibody formulations are described in U.S. Pat.No. 6,267,958. Aqueous antibody formulations include those described inU.S. Pat. No. 6,171,586 and WO2006/044908, the latter formulationsincluding a histidine-acetate buffer.

The formulation herein may also contain more than one active ingredientsas necessary for the particular indication being treated, preferablythose with complementary activities that do not adversely affect eachother. For example, it may be desirable to further provide an additionaltherapeutic agent (e.g., a chemotherapeutic agent, a cytotoxic agent, agrowth inhibitory agent, and/or an anti-hormonal agent, such as thoserecited herein above). Such active ingredients are suitably present incombination in amounts that are effective for the purpose intended.

Active ingredients may be entrapped in microcapsules prepared, forexample, by coacervation techniques or by interfacial polymerization,for example, hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacylate) microcapsules, respectively, in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington's Pharmaceutical Sciences16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the antibody, which matrices are in theform of shaped articles, for example, films, or microcapsules.

The formulations to be used for in vivo administration are generallysterile. Sterility may be readily accomplished, e.g., by filtrationthrough sterile filtration membranes.

G. Therapeutic Methods and Compositions

Any of the anti-CD3 antibodies of the invention (e.g., bispecificanti-CD3 antibodies of the invention that bind to CD3 and a secondbiological molecule, e.g., a cell surface antigen, e.g., a tumorantigen, such as TDB antibodies of the invention or variants thereof)may be used in therapeutic methods.

In one aspect, an anti-CD3 antibody for use as a medicament is provided.In further aspects, an anti-CD3 antibody for use in treating or delayingprogression of a cell proliferative disorder (e.g., cancer) or anautoimmune disorder (e.g., arthritis) is provided. In certainembodiments, an anti-CD3 antibody for use in a method of treatment isprovided. In certain embodiments, the invention provides an anti-CD3antibody for use in a method of treating an individual having a cellproliferative disorder or an autoimmune disorder comprisingadministering to the individual an effective amount of the anti-CD3antibody. In one such embodiment, the method further comprisesadministering to the individual an effective amount of at least oneadditional therapeutic agent, for example, as described below. Infurther embodiments, the invention provides an anti-CD3 antibody for usein enhancing immune function in an individual having a cellproliferative disorder or an autoimmune disorder. In certainembodiments, the invention provides an anti-CD3 antibody for use in amethod of enhancing immune function in an individual having a cellproliferative disorder or an autoimmune disorder comprisingadministering to the individual an effective of the anti-CD3 antibody toactivate effector cells (e.g., T cells, e.g., CD8+ and/or CD4+ T cells),expand (increase) an effector cell population, reduce a target cell(e.g., a cell expressing a second biological molecule recognized by ananti-CD3 antibody of the invention, such as a bispecific TDB antibody ofthe invention) population, and/or kill a target cell (e.g., target tumorcell). An “individual” according to any of the above embodiments may bea human.

In a further aspect, the invention provides for the use of an anti-CD3antibody in the manufacture or preparation of a medicament. In oneembodiment, the medicament is for treatment of a cell proliferativedisorder (e.g., cancer) or an autoimmune disorder (e.g., arthritis). Ina further embodiment, the medicament is for use in a method of treatinga cell proliferative disorder or an autoimmune disorder comprisingadministering to an individual having a cell proliferative disorder oran autoimmune disorder an effective amount of the medicament. In onesuch embodiment, the method further comprises administering to theindividual an effective amount of at least one additional therapeuticagent, for example, as described below. In a further embodiment, themedicament is for activating effector cells (e.g., T cells, e.g., CD8+and/or CD4+ T cells), expanding (increasing) an effector cellpopulation, reducing a target cell (e.g., a cell expressing a secondbiological molecule recognized by an anti-CD3 antibody of the invention,such as a bispecific TDB antibody of the invention) population, and/orkilling target cells (e.g., target tumor cells) in the individual. In afurther embodiment, the medicament is for use in a method of enhancingimmune function in an individual having a cell proliferative disorder oran autoimmune disorder comprising administering to the individual anamount effective of the medicament to activate effector cells (e.g., Tcells, e.g., CD8+ and/or CD4+ T cells), expand (increase) an effectorcell population, reduce a target cell (e.g., a cell expressing a secondbiological molecule recognized by an anti-CD3 antibody of the invention,such as a bispecific TDB antibody of the invention) population, and/orkill a target cell (e.g., target tumor cell). An “individual” accordingto any of the above embodiments may be a human.

In a further aspect, the invention provides a method for treating a cellproliferative disorder (e.g., cancer) or an autoimmune disorder (e.g.,arthritis). In one embodiment, the method comprises administering to anindividual having such a cell proliferative disorder or an autoimmunedisorder an effective amount of an anti-CD3 antibody. In one suchembodiment, the method further comprises administering to the individualan effective amount of at least one additional therapeutic agent, forexample, as described below. An “individual” according to any of theabove embodiments may be a human.

In a further aspect, the invention provides a method for enhancingimmune function in an individual having a cell proliferative disorder oran autoimmune disorder in an individual having a cell proliferativedisorder or an autoimmune disorder. In one embodiment, the methodcomprises administering to the individual an effective amount of ananti-CD3 antibody to activate effector cells (e.g., T cells, e.g., CD8+and/or CD4+ T cells), expand (increase) an effector cell population,reduce a target cell (e.g., a cell expressing a second biologicalmolecule recognized by an anti-CD3 antibody of the invention, such as abispecific TDB antibody of the invention) population, and/or kill atarget cell (e.g., target tumor cell). In one embodiment, an“individual” is a human.

In a further aspect, the invention provides a method for treating ahematological cancer, such as a B cell cancer (for example, matureB-cell lymphoma) by administering an effective amount of an anti-CD3antibody of the invention, such as a bispecific TDB antibody of theinvention, such as an anti-B cell targeting TDB, such as a CD20-TDBhaving an anti-CD3 arm and an anti-CD20 arm. In a further aspect of theembodiment, the mature B-cell lymphoma is a Non-Hodgkin's Lymphoma(NHL). In a further aspect of the embodiment, the NHL is selected fromthe group comprising: germinal-center B-cell-like (GCB) DLBCL, activatedB-cell-like (ABC) DLBCL, follicular lymphoma (FL), mantle cell lymphoma(MCL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL),marginal zone lymphoma (MZL), small lymphocytic leukemia (SLL),lymphoplasmacytic lymphoma (LL), Waldenstrom macroglobulinemia (WM),central nervous system lymphoma (CNSL), Burkitt's lymphoma (BL), B-cellprolymphocytic leukemia, Splenic marginal zone lymphoma, Hairy cellleukemia, Splenic lymphoma/leukemia, unclassifiable, Splenic diffuse redpulp small B-cell lymphoma, Hairy cell leukemia variant, Waldenströmmacroglobulinemia, Heavy chain diseases, a Heavy chain disease, γ Heavychain disease, μ Heavy chain disease, Plasma cell myeloma, Solitaryplasmacytoma of bone, Extraosseous plasmacytoma, Extranodal marginalzone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma),Nodal marginal zone lymphoma, Pediatric nodal marginal zone lymphoma,Pediatric follicular lymphoma, Primary cutaneous follicle centrelymphoma, T-cell/histiocyte rich large B-cell lymphoma, Primary DLBCL ofthe CNS, Primary cutaneous DLBCL, leg type, EBV-positive DLBCL of theelderly, DLBCL associated with chronic inflammation, Lymphomatoidgranulomatosis, Primary mediastinal (thymic) large B-cell lymphoma,Intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma,Plasmablastic lymphoma, Large B-cell lymphoma arising in HHV8-associatedmulticentric Castleman disease, Primary effusion lymphoma: B-celllymphoma, unclassifiable, with features intermediate between diffuselarge B-cell lymphoma and Burkitt lymphoma, and B-cell lymphoma,unclassifiable, with features intermediate between diffuse large B-celllymphoma and classical Hodgkin lymphoma. In a preferred embodiment ofthe invention, the method comprises treating a cancer comprisinggerminal-center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC)DLBCL, follicular lymphoma (FL), mantle cell lymphoma (MCL), acutemyeloid leukemia (AML), chronic lymphoid leukemia (CLL), marginal zonelymphoma (MZL), small lymphocytic leukemia (SLL), lymphoplasmacyticlymphoma (LL), Waldenstrom macroglobulinemia (WM), central nervoussystem lymphoma (CNSL), or Burkitt's lymphoma (BL).

In one embodiment, the method comprises administering to an individualhaving such a hematological cancer (for example, B cell cancer, forexample, B cell lymphoma) an effective amount of an anti-CD3 antibody ofthe invention, such as a bispecific TDB antibody, such as a CD20 TDBcomprising an anti-CD20 targeting arm and an anti-CD3 targeting arm. Inother embodiments, a CD20 TDB is co-administered with one or moreadditional therapeutic agents. In one embodiment, the therapeutic agentis an antibody targeting CD20. In one embodiment, a CD20 TDB isco-administered with one or more antibodies targeting CD20 selected fromthe chimeric monoclonal CD20 antibody, rituximab (Rituxan®) or themonoclonal CD20 antibody, obinutuzumab (Gazyva®). In one embodiment, aCD20 TDB is co-administered with rituximab. In one embodiment, a CD20TDB is co-administered with obinutuzumab. In one embodiment, a CD20 TDBis co-administered with obinutuzumab and rituximab.

In one further embodiment, the anti-CD3 antibody of the invention (forexample, the CD20 TDB), with or without a CD20 monoclonal antibody, isadministered with a further chemotherapy agent and/or an antibody-drugconjugate (ADC). In one embodiment, a CD20 TDB is co-administered withone or more additional chemotherapy agents selected fromcyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP). Inone embodiment, a CD20 TDB is co-administered with an ADC. In oneembodiment, a CD20 TDB is co-administered with CHOP, wherein vincristineis replaced with an ADC. In one embodiment, a CD20 TDB isco-administered with an ADC selected from an anti-CD79b antibody drugconjugate (such as anti-CD79b-MC-vc-PAB-MMAE or the anti-CD79b antibodydrug conjugate described in any one of U.S. Pat. No. 8,088,378 and/or US2014/0030280, or polatuzumab vedotin), an anti-CD19 antibody drugconjugate, an anti-CD22 antibody drug conjugate, an anti-CD45 antibodydrug conjugate, and an anti-CD32 drug conjugate.

In one other embodiment the therapeutic agent is a biological modifier.In one embodiment, a CD20 TDB is co-administered with one or morebiological modifiers selected from a BCL-2 inhibitor (such asGDC-0199/ABT-199), lenalidomide (Revlimid®), a PI3K-delta inhibitor(such as idelalisib (Zydelig®)), a PD-1 axis binding antagonist, anagonist, e.g., agonist antibody, directed against an activatingco-stimulatory molecule, e.g., CD40, CD226, CD28, OX40 (e.g., AgonOX),GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (e.g.,CDX-1127), HVEM, or CD127, an antagonist, e.g., antagonist antibody,directed against an inhibitory co-stimulatory molecule, e.g., CTLA-4(also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4,IDO (e.g., 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B,GITR (e.g., TRX518) or arginase, ipilimumab (also known as MDX-010,MDX-101, or Yervoy®), tremelimumab (also known as ticilimumab orCP-675,206, urelumab (also known as BMS-663513), MGA271, an antagonistdirected against a TGF beta, e.g., metelimumab (also known as CAT-192),fresolimumab (also known as GC1008), LY2157299k, and an adoptivetransfer of a T cell (e.g., a cytotoxic T cell or CTL) expressing achimeric antigen receptor (CAR), e.g., adoptive transfer of a T cellcomprising a dominant-negative TGF beta receptor, e.g, adominant-negative TGF beta type II receptor.

In one embodiment, a CD20 TDB is co-administered with rituximab and oneor more chemotherapy agents. In one such embodiment, a CD20 TDB isco-administered with rituximab and CHOP. In one embodiment, a CD20 TDBis co-administered with rituximab and an ADC. In one embodiment, a CD20TDB is co-administered with rituximab and CHOP, wherein vincristine isreplaced with an ADC. In one embodiment, a CD20 TDB is co-administeredwith an ADC selected from an anti-CD79b antibody drug conjugate (such asanti-CD79b-MC-vc-PAB-MMAE or the anti-CD79b antibody drug conjugatedescribed in any one of U.S. Pat. No. 8,088,378 and/or US 2014/0030280,or polatuzumab vedotin), an anti-CD19 antibody drug conjugate, ananti-CD22 antibody drug conjugate, an anti-CD45 antibody drug conjugate,and an anti-CD32 drug conjugate. In one embodiment, a CD20 TDB isco-administered with rituximab and one or more biological modifiersselected from a BCL-2 inhibitor (such as GDC-0199/ABT-199), lenalidomide(Revlimid®), a PI3K-delta inhibitor (such as idelalisib (Zydelig®)), aPD-1 axis binding antagonist, an agonist, e.g., agonist antibody,directed against an activating co-stimulatory molecule, e.g., CD40,CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known as TNFRSF9,4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127, an antagonist,e.g., antagonist antibody, directed against an inhibitory co-stimulatorymolecule, e.g., CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA,LAG-3, B7-H3, B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase, ipilimumab(also known as MDX-010, MDX-101, or Yervoy®), tremelimumab (also knownas ticilimumab or CP-675,206, urelumab (also known as BMS-663513),MGA271, an antagonist directed against a TGF beta, e.g., metelimumab(also known as CAT-192), fresolimumab (also known as GC1008),LY2157299k, and an adoptive transfer of a T cell (e.g., a cytotoxic Tcell or CTL) expressing a chimeric antigen receptor (CAR), e.g.,adoptive transfer of a T cell comprising a dominant-negative TGF betareceptor, e.g, a dominant-negative TGF beta type II receptor.

In one embodiment, a CD20 TDB is co-administered with rituximab, one ormore chemotherapy agents, and one or more biological modifiers selectedfrom a BCL-2 inhibitor (such as GDC-0199/ABT-199), lenalidomide(Revlimid®), a PI3K-delta inhibitor (such as idelalisib (Zydelig®)), aPD-1 axis binding antagonist, an agonist, e.g., agonist antibody,directed against an activating co-stimulatory molecule, e.g., CD40,CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known as TNFRSF9,4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127, an antagonist,e.g., antagonist antibody, directed against an inhibitory co-stimulatorymolecule, e.g., CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA,LAG-3, B7-H3, B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as1-D-MT)), TIGIT, MICA/B, GITR (e.g., TRX518) or arginase, ipilimumab(also known as MDX-010, MDX-101, or Yervoy®), tremelimumab (also knownas ticilimumab or CP-675,206, urelumab (also known as BMS-663513),MGA271, an antagonist directed against a TGF beta, e.g., metelimumab(also known as CAT-192), fresolimumab (also known as GC1008),LY2157299k, and an adoptive transfer of a T cell (e.g., a cytotoxic Tcell or CTL) expressing a chimeric antigen receptor (CAR), e.g.,adoptive transfer of a T cell comprising a dominant-negative TGF betareceptor, e.g, a dominant-negative TGF beta type II receptor.

In one embodiment, a CD20 TDB is co-administered with rituximab, an ADC,and one or more biological modifiers selected from a BCL-2 inhibitor(such as GDC-0199/ABT-199), lenalidomide (Revlimid®), a PI3K-deltainhibitor (such as idelalisib (Zydelig®)), a PD-1 axis bindingantagonist, an agonist, e.g., agonist antibody, directed against anactivating co-stimulatory molecule, e.g., CD40, CD226, CD28, OX40 (e.g.,AgonOX), GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27 (e.g.,CDX-1127), HVEM, or CD127, an antagonist, e.g., antagonist antibody,directed against an inhibitory co-stimulatory molecule, e.g., CTLA-4(also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4,IDO (e.g., 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B,GITR (e.g., TRX518) or arginase, ipilimumab (also known as MDX-010,MDX-101, or Yervoy®), tremelimumab (also known as ticilimumab orCP-675,206, urelumab (also known as BMS-663513), MGA271, an antagonistdirected against a TGF beta, e.g., metelimumab (also known as CAT-192),fresolimumab (also known as GC1008), LY2157299k, and an adoptivetransfer of a T cell (e.g., a cytotoxic T cell or CTL) expressing achimeric antigen receptor (CAR), e.g., adoptive transfer of a T cellcomprising a dominant-negative TGF beta receptor, e.g, adominant-negative TGF beta type II receptor.

In one embodiment, a CD20 TDB is co-administered with obinutuzumab andone or more chemotherapy agents. In one embodiment, a CD20 TDB isco-administered with obinutuzumab and CHOP. In one embodiment, a CD20TDB is co-administered with obinutuzumab and an ADC. In one embodiment,a CD20 TDB is co-administered with obinutuzumab and CHOP, whereinvincristine is replaced with an ADC. In one embodiment, a CD20 TDB isco-administered with an ADC selected from an anti-CD79b antibody drugconjugate (such as anti-CD79b-MC-vc-PAB-MMAE or the anti-CD79b antibodydrug conjugate described in any one of U.S. Pat. No. 8,088,378 and/or US2014/0030280, or polatuzumab vedotin), an anti-CD19 antibody drugconjugate, an anti-CD22 antibody drug conjugate, an anti-CD45 antibodydrug conjugate, and an anti-CD32 drug conjugate. In one embodiment, aCD20 TDB is co-administered with obinutuzumab and one or more biologicalmodifiers selected from a BCL-2 inhibitor (such as GDC-0199/ABT-199),lenalidomide (Revlimid®), a PI3K-delta inhibitor (such as idelalisib(Zydelig®)), a PD-1 axis binding antagonist, an agonist, e.g., agonistantibody, directed against an activating co-stimulatory molecule, e.g.,CD40, CD226, CD28, OX40 (e.g., AgonOX), GITR, CD137 (also known asTNFRSF9, 4-1BB, or ILA), CD27 (e.g., CDX-1127), HVEM, or CD127, anantagonist, e.g., antagonist antibody, directed against an inhibitoryco-stimulatory molecule, e.g., CTLA-4 (also known as CD152), PD-1,TIM-3, BTLA, VISTA, LAG-3, B7-H3, B7-H4, IDO (e.g.,1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT, MICA/B, GITR(e.g., TRX518) or arginase, ipilimumab (also known as MDX-010, MDX-101,or Yervoy®), tremelimumab (also known as ticilimumab or CP-675,206,urelumab (also known as BMS-663513), MGA271, an antagonist directedagainst a TGF beta, e.g., metelimumab (also known as CAT-192),fresolimumab (also known as GC1008), LY2157299k, and an adoptivetransfer of a T cell (e.g., a cytotoxic T cell or CTL) expressing achimeric antigen receptor (CAR), e.g., adoptive transfer of a T cellcomprising a dominant-negative TGF beta receptor, e.g, adominant-negative TGF beta type II receptor.

In one embodiment, a CD20 TDB is co-administered with obinutuzumab, anADC, and one or more biological modifiers selected from a BCL-2inhibitor (such as GDC-0199/ABT-199), lenalidomide (Revlimid®), aPI3K-delta inhibitor (such as idelalisib (Zydelig®)), a PD-1 axisbinding antagonist, an agonist, e.g., agonist antibody, directed againstan activating co-stimulatory molecule, e.g., CD40, CD226, CD28, OX40(e.g., AgonOX), GITR, CD137 (also known as TNFRSF9, 4-1BB, or ILA), CD27(e.g., CDX-1127), HVEM, or CD127, an antagonist, e.g., antagonistantibody, directed against an inhibitory co-stimulatory molecule, e.g.,CTLA-4 (also known as CD152), PD-1, TIM-3, BTLA, VISTA, LAG-3, B7-H3,B7-H4, IDO (e.g., 1-methyl-D-tryptophan (also known as 1-D-MT)), TIGIT,MICA/B, GITR (e.g., TRX518) or arginase, ipilimumab (also known asMDX-010, MDX-101, or Yervoy®), tremelimumab (also known as ticilimumabor CP-675,206, urelumab (also known as BMS-663513), MGA271, anantagonist directed against a TGF beta, e.g., metelimumab (also known asCAT-192), fresolimumab (also known as GC1008), LY2157299k, and anadoptive transfer of a T cell (e.g., a cytotoxic T cell or CTL)expressing a chimeric antigen receptor (CAR), e.g., adoptive transfer ofa T cell comprising a dominant-negative TGF beta receptor, e.g, adominant-negative TGF beta type II receptor.

In a further aspect of the invention, the additional therapy comprisesan anti-CD20 antibody. In one embodiment, the anti-CD20 antibody isrituximab. In one embodiment, the anti-CD20 antibody is a humanizedB-Ly1 antibody. In one embodiment, the humanized B-Ly1 antibody isobinituzumab. In one embodiment, the anti-CD20 antibody is ofatumumab,ublituximab, and/or ibritumomab tiuxetan.

In a further aspect of the invention, the additional therapy comprisesan alkylating agent. In one embodiment, the alkylating agent is4-[5-[Bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acidand salts thereof. In one embodiment, the alkylating agent isbendamustine.

In a further aspect of the invention, the additional therapy comprises aBCL-2 inhibitor. In one embodiment, the BCL-2 inhibitor is4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideand salts thereof. In one embodiment, the BCL-2 inhibitor is venetoclax(CAS #: 1257044-40-8).

In a further aspect of the invention, the additional therapy comprises aphosphoinositide 3-kinase (PI3K) inhibitor. In one embodiment, the PI3Kinhibitor inhibits delta isoform PI3K (i.e., P110δ). In someembodiments, the PI3K inhibitor is 5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone and salts thereof.In some embodiments, the PI3K inhibitor is idelalisib (CAS #:870281-82-6). In one embodiment, the PI3K inhibitor inhibits alpha anddelta isoforms of PI3K. In some embodiments, the PI3K inhibitor is2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamideand salts thereof.

In a further aspect of the invention, the additional therapy comprises aBruton's tyrosine kinase (BTK) inhibitor. In one embodiment, the BTKinhibitor is1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-oneand salts thereof. In one embodiment, the BTK inhibitor is ibrutinib(CAS #: 936563-96-1).

In a further aspect of the invention, the additional therapy comprisesthalidomide or a derivative thereof. In one embodiment, the thalidomideor a derivative thereof is (RS)-3-(4-Amino-1-oxo1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione and salts thereof. Inone embodiment, the thalidomide or a derivative thereof is lendalidomide(CAS #: 191732-72-6).

In a further aspect of the invention, the additional therapy comprisesone or more of cyclophosphamide, doxorubicin, vincristine, orprednisolone (CHOP). In one embodiment, the additional therapy furthercomprises an anti-CD20 antibody as described above (e.g., GA-101 and/orRituxan®).

Any of the above methods and therapies may be used, without limitation,for any cancer, including, for example, treatment of a B-cell cancer orbreast cancer.

In a further aspect, the invention provides a method for treatingHER2-positive cancers. In one embodiment, the method comprisesadministering to an individual having such a cancer an effective amountof an anti-HER2 antibody of the invention, such as a bispecific TDBantibody with an anti-HER2 targeting arm and an anti-CD3 targeting arm.In a preferred embodiment, the HER2-TDB possesses an acceptable toxicityprofile when administered in an effective dose in a patient. In oneembodiment, the CD3 arm of the HER2-TDB with an acceptable toxicityprofile is a low affinity CD3 arm. In one embodiment, the CD3 arm of theHER2-TDB with an acceptable toxicity profile is 40G5c.

In a preferable embodiment, the HER2-positive cancer is a HER2-positivebreast cancer or HER2-positive gastric cancer. In one embodiment, a HER2TDB is co-administered with one or more additional therapeutic agentsthat target the HER pathway. In one embodiment, the therapeutic agentthat targets the HER pathway is selected from an EGFR inhibitor, a HER2inhibitor, a HER3 inhibitor, and/or a HER4 inhibitor. In one embodiment,a HER2 TDB is co-administered with one or more additional therapeuticagents selected from trastuzumab (Herceptin®), T-DM1 (Kadcyla®) andpertuzumab (Perjeta®). In one embodiment, a HER2 TDB is co-administeredwith trastuzumab. In one embodiment, a HER2 TDB is co-administered withT-DM1. In one embodiment, a HER2 TDB is co-administered with pertuzumab.In one embodiment, a HER2 TDB is co-administered with trastuzumab andpertuzumab. In one embodiment, a HER2 TDB is co-administered with T-DM1and pertuzumab.

In a further aspect, the invention provides pharmaceutical formulationscomprising any of the anti-CD3 antibodies provided herein, e.g., for usein any of the above therapeutic methods. In one embodiment, apharmaceutical formulation comprises any of the anti-CD3 antibodiesprovided herein and a pharmaceutically acceptable carrier. In anotherembodiment, a pharmaceutical formulation comprises any of the anti-CD3antibodies provided herein and at least one additional therapeuticagent, for example, as described herein.

Antibodies of the invention can be used either alone or in combinationwith other agents in a therapy. For instance, an antibody of theinvention may be co-administered with at least one additionaltherapeutic agent. In certain embodiments, an additional therapeuticagent is a chemotherapeutic agent, growth inhibitory agent, cytotoxicagent, agent used in radiation therapy, anti-angiogenesis agent,apoptotic agent, anti-tubulin agent, or other agent, such as a epidermalgrowth factor receptor (EGFR) antagonist (e.g., a tyrosine kinaseinhibitor), HER1/EGFR inhibitor (e.g., erlotinib (Tarceva™), plateletderived growth factor inhibitor (e.g., Gleevec™ (Imatinib Mesylate)), aCOX-2 inhibitor (e.g., celecoxib), interferon, cytokine, antibody otherthan the anti-CD3 antibody of the invention, such as an antibody thatbind to one or more of the following targets ErbB2, ErbB3, ErbB4,PDGFR-beta, BlyS, APRIL, BCMA VEGF, or VEGF receptor(s), TRAIL/Apo2,PD-1, PD-L1, PD-L2, or another bioactive or organic chemical agent.

In some embodiments, the invention provides a method wherein theadditional therapeutic agent is a glucocorticoid. In one embodiment, theglucocorticoid is dexamethasone.

Such combination therapies noted above encompass combined administration(where two or more therapeutic agents are included in the same orseparate formulations), and separate administration, in which case,administration of the antibody of the invention can occur prior to,simultaneously, and/or following, administration of the additionaltherapeutic agent or agents. In one embodiment, administration of theanti-CD3 antibody and administration of an additional therapeutic agentoccur within about one month, or within about one, two or three weeks,or within about one, two, three, four, five, or six days, of each other.Anti-CD3 antibodies of the invention (e.g., bispecific anti-CD3antibodies of the invention that bind to CD3 and a second biologicalmolecule, e.g., a cell surface antigen, e.g., a tumor antigen, such as aTDB antibody of the invention or variant thereof) can also be used incombination with radiation therapy.

An antibody of the invention (and/or any additional therapeutic agent)can be administered by any suitable means, including parenteral,intrapulmonary, and intranasal, and, if desired for local treatment,intralesional administration. Parenteral infusions includeintramuscular, intravenous, intraarterial, intraperitoneal, orsubcutaneous administration. In some embodiments, the antibody isadministered by subcutaneous administration. In some embodiments, ananti-CD3 antibody administered by subcutaneous injection exhibits a lesstoxic response in a patient than the same anti-CD3 antibody administeredby intravenous injection. Dosing can be by any suitable route, forexample, by injections, such as intravenous or subcutaneous injections,depending in part on whether the administration is brief or chronic.Various dosing schedules including but not limited to single or multipleadministrations over various time-points, bolus administration, andpulse infusion are contemplated herein.

Antibodies of the invention would be formulated, dosed, and administeredin a fashion consistent with good medical practice. Factors forconsideration in this context include the particular disorder beingtreated, the particular mammal being treated, the clinical condition ofthe individual patient, the cause of the disorder, the site of deliveryof the agent, the method of administration, the scheduling ofadministration, and other factors known to medical practitioners. Theantibody need not be, but is optionally formulated with one or moreagents currently used to prevent or treat the disorder in question. Theeffective amount of such other agents depends on the amount of antibodypresent in the formulation, the type of disorder or treatment, and otherfactors discussed above. These are generally used in the same dosagesand with administration routes as described herein, or about from 1 to99% of the dosages described herein, or in any dosage and by any routethat is empirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of anantibody of the invention (when used alone or in combination with one ormore other additional therapeutic agents) will depend on the type ofdisease to be treated, the type of antibody, the severity and course ofthe disease, whether the antibody is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the antibody, and the discretion of the attendingphysician. The antibody is suitably administered to the patient at onetime or over a series of treatments.

As a general proposition, the therapeutically effective amount of theanti-CD3 antibody administered to human will be in the range of about0.01 to about 100 mg/kg of patient body weight whether by one or moreadministrations. In some embodiments, the antibody used is about 0.01 toabout 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about0.01 to about 20 mg/kg, about 0.01 to about 15 mg/kg, about 0.01 toabout 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1mg/kg administered daily, for example. In one embodiment, an anti-CD3antibody described herein is administered to a human at a dose of about100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about1100 mg, about 1200 mg, about 1300 mg or about 1400 mg on day 1 of21-day cycles. The dose may be administered as a single dose or asmultiple doses (e.g., 2 or 3 doses), such as infusions. For repeatedadministrations over several days or longer, depending on the condition,the treatment would generally be sustained until a desired suppressionof disease symptoms occurs. One exemplary dosage of the antibody wouldbe in the range from about 0.05 mg/kg to about 10 mg/kg. Thus, one ormore doses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or anycombination thereof) may be administered to the patient. Such doses maybe administered intermittently, for example, every week or every threeweeks (e.g., such that the patient receives from about two to abouttwenty, or, for example, about six doses of the anti-CD3 antibody). Aninitial higher loading dose, followed by one or more lower doses may beadministered. The progress of this therapy is easily monitored byconventional techniques and assays.

In some embodiments, the methods may further comprise an additionaltherapy. The additional therapy may be radiation therapy, surgery,chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy,immunotherapy, bone marrow transplantation, nanotherapy, monoclonalantibody therapy, or a combination of the foregoing. The additionaltherapy may be in the form of adjuvant or neoadjuvant therapy. In someembodiments, the additional therapy is the administration of smallmolecule enzymatic inhibitor or anti-metastatic agent. In someembodiments, the additional therapy is the administration of side-effectlimiting agents (e.g., agents intended to lessen the occurrence and/orseverity of side effects of treatment, such as anti-nausea agents,etc.). In some embodiments, the additional therapy is radiation therapy.In some embodiments, the additional therapy is surgery. In someembodiments, the additional therapy is a combination of radiationtherapy and surgery. In some embodiments, the additional therapy isgamma irradiation. In some embodiments, the additional therapy may be aseparate administration of one or more of the therapeutic agentsdescribed above.

H. Articles of Manufacture

In another aspect of the invention, an article of manufacture containingmaterials useful for the treatment, prevention and/or diagnosis of thedisorders described above is provided. The article of manufacturecomprises a container and a label or package insert on or associatedwith the container. Suitable containers include, for example, bottles,vials, syringes, IV solution bags, etc. The containers may be formedfrom a variety of materials such as glass or plastic. The containerholds a composition which is by itself or combined with anothercomposition effective for treating, preventing and/or diagnosing thecondition and may have a sterile access port (for example the containermay be an intravenous solution bag or a vial having a stopper pierceableby a hypodermic injection needle). At least one active agent in thecomposition is an antibody of the invention. The label or package insertindicates that the composition is used for treating the condition ofchoice. Moreover, the article of manufacture may comprise (a) a firstcontainer with a composition contained therein, wherein the compositioncomprises an antibody of the invention; and (b) a second container witha composition contained therein, wherein the composition comprises afurther cytotoxic or otherwise therapeutic agent. The article ofmanufacture in this embodiment of the invention may further comprise apackage insert indicating that the compositions can be used to treat aparticular condition. Alternatively, or additionally, the article ofmanufacture may further comprise a second (or third) containercomprising a pharmaceutically-acceptable buffer, such as bacteriostaticwater for injection (BWFI), phosphate-buffered saline, Ringer's solutionand dextrose solution. It may further include other materials desirablefrom a commercial and user standpoint, including other buffers,diluents, filters, needles, and syringes.

III. Examples

The following are examples of methods and compositions of the invention.It is understood that various other embodiments may be practiced, giventhe general description provided above.

Example 1. Generation of Anti-CD3 Antibodies

CD3ε Antigens

A. Bispecific Human and Cyno CD3ε+CD3γ Fused to Mouse IgG2a-Fc(CD3εγ-muFc)

cDNA encoding extracellular portions of human or cynomolgus monkey(cyno) CD3ε or CD3γ was fused at the C-terminus to a mouse IgG2a Fc togenerate CD3-Fc fusions. The cDNAs encoding extracellular domains ofhuman or cyno CD3ε and CD3γ were generated using total RNA fromanti-CD3/anti-CD28-activated peripheral blood mononuclear cells (PBMCs).Normal PBMCs were activated by plate-immobilized anti-CD3 and anti-CD28in RPMI supplemented with 10% FBS for 72h. Total mRNA was isolated usingan RNeasy mini kit from Qiagen. cDNA was cloned using gene-specificprimers by RT-PCR into TOPO vectors using Taq polymerase-amplified PCRproducts following the protocol provided with the TOPO TA cloning kitfrom Invitrogen. The resulting fragments were introduced into amammalian expression vector containing a murine IgG2a Fc domain byrestriction-free subcloning using Phusion High-Fidelity DNA Polymerase(New England Biolabs, Catalog #M0530L). The CD3 fragments were thusamplified with overlapping regions contained in the template plasmid toorient them directly downstream of the signal sequence and N-terminal tothe murine Fc.

For both human and cyno constructs, the CD3ε-Fc containing plasmid wastransiently co-expressed with the CD3γ-Fc containing plasmid inmammalian CHO cells. Heterodimers of CD3ε/γ were purified by ProteinA-Sepharose (Pharmacia Biotech).

B. N-Terminal Peptide-KLH Conjugates (CD3ε-KLH)

Peptide fragments containing N-terminal sequences of cyno and human CD3εwere synthesized. The fragments intended for immunization wereconjugated to keyhole limpet hemocyanin (KLH), a widely used carrierprotein for generating a substantial immune response. Appending thenaturally occurring cysteine at position 28 for cyno and human CD3εallowed for coupling of maleimide-activated KLH to the thiol-containingC-terminal cysteine.

C. Single Chain CD3ε-26Mer-CD3γ (CD3εγ)

The cDNAs encoding extracellular portions of human CD3ε and CD3γsubunits were generated by PCR. Amino acids 1-97 of human CD3ε and aminoacids 1-81 of human CD3γ were connected using a flexible peptide linkerof 26 amino acids to form a CD3ε-26mer-CD3γ construct (CD3εγ) (FIG. 1 ).The construct was cloned into an expression vector with a His-tag forsecretion from E. coli using the alkaline phosphotase promoter and theSTIII secretion signal sequence. CD3εγ was purified on a Ni column andsubsequently refolded. Properly folded CD3εγ was then purified using anOKT3 affinity column.

In addition for some binding experiments, commercial CD3ε was purchasedfrom Creative Biomart, Shirley, N.Y. 11967 (Catalog number CD3ε-2194H).

Immunizations

A. Mouse Immunizations

BALB/c or C57BL/6 mice were immunized (2 μg or 10 μg/injection permouse). Antigens, suspended in monophosphoryl lipid A/trehalosedicorynomycolate adjuvant, were injected into the footpad at 3- to 4-dayintervals for a total of 12-15 boosts. Three days after the finalpre-fusion boost, lymphocytes from immunized mice spleens and lymphnodes were harvested. Isolated mouse lymphocytes were fused withSP2/0-Ag14 myeloma cells (American Type Culture Collection) by using theCyto Pulse CEEF-50 apparatus (Cyto Pulse Sciences). Briefly, afterwashing twice with Cytofusion Medium C (Cat #LCM-C), the isolated spleencells and SP2/0-Ag14 cells were mixed at a 1:1 ratio and then suspendedat 10 million cells/ml in Cytofusion Medium C, electrofusion wasperformed according to manufacturer's guidance. Fused cells werecultured in ClonaCell-HY Medium C (Cat #03803) overnight at 37° C. in a7% CO₂ incubator. Next day the fused cells were centrifuged and thensuspended in 10 ml ClonaCell-HY Medium C and then gently mixed with 90ml Methylcellulose-based ClonaCell-HY Medium D (Cat #03804) containingHAT components. The cells were plated into OmniTray plates (ThermoScientific) and allowed to grow in 37° C. in a 7% CO₂ incubator. After6-7 days incubation, single hybridoma clones were picked by ClonePix FL(Molecular Devices) and transferred into 96-well cell culture plates(#353075, Becton Dickinson) with 200 μL/well ClonaCell-HY Medium E (Cat#03805). Hybridoma culture media were changed prior to ELISA screening.

B. Rabbit Immunizations

Rabbit immunizations were performed using 0.5 mg/injection with CFA/IFAhuman and cyno CD3ε-KLH every 2 weeks for 5 injections (d0, d14, d28,d42, d56). Bleeds were taken on days 52 and 66.

PEG fusions and screening was performed as follows. Clones were screenedfor binding to the N-terminal portion of CD3ε conjugated tothyroglobulin (THY) by ELISA. All positive clones were also found tocross-react with cyno CD3ε by ELISA and 16 unique clones were selectedfor sub-cloning. Total RNA was extracted from frozen cell pellets andpurified using a Qiagen RNeasy kit following manufacturer'sinstructions. First strand cDNA was synthesized using RT-PCR one-step(Qiagen). Rabbit VH and VL domains were further PCR amplified using aprotocol described for generating rabbit immune libraries (Kontermannand Dubel. Antibody Engineering. 1: 115-123, 2010). Moderate degeneracywas designed to represent common rabbit germline immunoglobulin genes.

Antibody Screening

A. Mouse hybridoma screening

3 days after media change, hybridoma supernatants were screened by ELISAfor binding to both human and cynoCD3ε, as described below. All ELISApositive clones were further screened by flow cytometry for binding tohuman Jurkat T cells, human PBMCs, and cyno PBMCs (FIGS. 2 and 3 ).Hybridoma supernatants were purified by Protein A affinitychromatography, then sterile filtered (0.2-μm pore size, Nalge NuncInternational, NY, USA) and stored at 4° C. in PBS. Purified mAbs wereconfirmed by ELISA before further testing in functional assays. mAbisotype was determined using a mouse monoclonal antibody isotyping kitfrom Roche Diagnostics Corporation.

The amino acid sequences of the light and heavy chain variable domainsof the anti-CD3 antibodies 13A3, 72H6, and 19B1 are shown in FIG. 4A.FIG. 4A also delimits the HVR sequences for each of the threeantibodies. FIGS. 4B, 4C, 5A, and 5B show additional amino acidsequences of the light and heavy chain variable domains of otheranti-CD3 antibodies.

B. Screening Following Rabbit Immunizations

Eight unique heavy chain sequences, and six unique light chain sequenceswere cloned out from the hybridoma cell lines. FIG. 7 shows the heavychain and light chain sequences for one of these antibodies, Rab17. Highsimilarity in sequence led to the decision to focus on 6 heavy and lightpairs. The 6 resulting antibodies were expressed as chimericrabbit/human IgGs on a small scale (100 ml cultures of 293S), andscreened for binding to CD3 epsilon by ELISA.

Antibody Characterization—Binding Affinity and T Cell ActivationActivity Assays

A. CD3εγ Binding ELISA Assay

The CD3εγ binding ELISA assay was performed in 96-well microtiter ELISAplates (Greiner, Germany) coated with either human/cyno CD3ε N-terminalamino acids conjugated to THY or human/cyno CD3ε/γ fused to murine Fc at2 μg/ml in 0.05 M carbonate buffer (pH 9.6), 4° C. overnight. Afterwashing three times with wash buffer (0.05% Tween 20 in PBS), plateswere blocked with 200 μL ELISA assay diluents with BSA. 100 μL ofcultured supernatants or diluted purified mAbs were added and incubatedfor 1 h at room temperature. The plates were washed three times andincubated with HRP conjugated Goat anti-mouse IgG Fc for 1 hour. Afterwashing three times, bound enzyme was detected by addition of 100μL/well TMB substrate (BioFX Laboratories, MD, USA) for 5 min. Thereactions were stopped by adding 100 μL/well of stop reagent (BioFX,Laboratories, MD, USA) and detection of color at A_(630 nm).

B. Flow Cytometry Analysis

Human Jurkat T cells, human PBMCs, or cyno PBMCs were washed twice withFACS staining buffer (phosphate-buffered saline containing 1% fetalbovine serum) and then suspended in FACS staining buffer to finalconcentration of 5×10⁶ cells/ml. 100 μl cells were added to U-bottom96-well tissue culture plate (#353077, Becton Dickinson), and 100 μlhybridoma supernatants or diluted purified mAbs were added. After 30 minincubation on ice, cells were washed twice with FACS staining buffer andsubsequently stained with FITC- or allophycocyanin (APC)-conjugated goatanti-mouse IgG antibody (#1012-11, Southern Biotech) at 1:300 dilutionfor 30 min. After washing twice with FACS staining buffer, cells wereanalyzed by FACSCalibur (BD Biosciences) flow cytometry. Data wasanalyzed using FlowJo software (Tree Star, Inc.).

C. Human T Cell Activation Assay

Human blood was collected in heparinized syringes, and PBMC wereisolated using Leucosep (Greiner Bio-one, cat #227290P) and Ficoll PaquePlus (GE Healthcare Biosciences, cat #95038-168), as recommended by themanufacture. Cells were washed in RPMI medium containing 10% FBS,supplemented with GlutaMax (Gibco, cat #35050-061), penicillin &streptomycin (Gibco, cat #15140-122), and ˜0.2 million suspended cellswere added to a 96-well U-bottom plate. Anti-CD3 antibodies were addedat between 10 and 0.01 μg/ml. After culturing for ˜20 hours, cells werewashed with FACS buffer (0.5% BSA, 0.05% Na Azide in PBS). Cells werethen stained with anti-CD69-FITC (BD, cat #555530), anti-CD25-PE (BD,cat #555432) anti-CD4-APC (BD, cat #555349) or anti-CD8-APC (BD, cat#555369) in FACS buffer, washed with FACS buffer and suspend in 100 ulof FACS buffer containing 1 μg/ml Propidium Iodide. Data was collectedon a FACSCalibur flow cytometer and analyzed using FlowJo. The extent ofT cell activation was determined comparing the percentage of CD69+ andCD25+ population in CD4+ or CD8+ T cells.

D. Cyno T Cell Activation Assay

Cyno blood was collected in heparinized tubes. Red blood cells werelysed twice with ACK red blood cell lysis buffer (0.874% NH4Cl, 0.1%KHCO3, 0.00368 EDTA Disodium). Cells were washed in RPMI mediumcontaining 10% FBS, supplemented with GlutaMax (Gibco, cat #35050-061),penicillin & streptomycin (Gibco, cat #15140-122), and ˜0.2 millionsuspended cells were added to a 96-well U-bottom plate. Anti-CD3antibodies were added at 10 μg/ml. After culturing for ˜20 hours, cellswere washed with FACS buffer (0.5% BSA, 0.05% Na Azide in PBS). Cellswere then stained with anti-CD69-FITC (BD, cat #555530), anti-CD25-PE(BD, cat #555432) anti-CD4-APC (BD, cat #551980) in FACS buffer, washedwith FACS buffer and suspend in 100 μg of FACS buffer containing 1 μg/mlPropidium Iodide. Data was collected on a FACSCalibur flow cytometer andanalyzed using FlowJo. The extent of T cell activation was determined bycomparing the percentage of CD69+ and CD25+ population in CD4+ T cells.

Generation of Anti-CD3 Antibody Variants

A. Cloning and Sequencing of Mouse CD3εγ Human/Cyno Cross-ReactiveHybridomas

Total RNA was extracted from mouse hybridoma cells with RNeasy kit(Qiagen), and first-strand cDNA was synthesized using a SuperScript IIIRT kit (Invitrogen). Antibody genes were amplified by error-proof Taqpolymerase PCR with 5′ degenerated primer mixture and 3′ Cγ-, Cκ-,Cλ-specific primers. PCR products were purified and the variable regionsof the antibody heavy and light chains were obtained by sequencing thePCR product. The variable regions of antibody heavy and light chainswere digested with appropriate restriction enzymes and cloned intorespective pRK expression vectors. The murine antibodies were expressedin 293 cells.

B. Humanization

Sequences of human/cyno CD3εγ cross-reactive hybridomas were aligned tothe most homologous human consensus or germline light and heavy variabledomains (FIG. 7 ). A consensus sequence called mu40G5c was derived fromlight and heavy chain variable domains of related hybridoma clones (FIG.7 ). Hypervariable regions (HVRs) were engineered into light and heavyhuman acceptor frameworks to generate humanized CDR-grafts (see, e.g.,FIGS. 8A-8F). Humanized variants were assessed in the form of Fabfragments or as IgG. VL domain positions 24-34 (L1), 50-56 (L2) and89-97 (L3) and VH domain positions 26-35 (H1), 50-65 (H2) and 95-102(H3) were used for the grafts (FIGS. 8A-8F). Additional variants thatincluded various combinations of one or more mouse vernier positionswere also generated and tested for binding affinity (see, e.g., FIGS.9A-9F). Murine variable domain residues at select vernier positions wereincorporated into a final humanized sequence based on their ability toimprove binding affinity. The monovalent binding affinities for selectedhumanized antibodies for different CD3ε antigens are shown in FIG. 10 .The binding affinities for affinity variants of humanized anti-CD3antibody 38E4 (38E4v1-38E4v9) and 40G5c are shown in FIG. 11 .

C. Paratope Mapping

Each residue in HVR-L3 and HVR-H3 of hu38E4 was separately mutated toalanine using Kunkle mutagenesis. In addition, position 95 in HVR-H3 wasalso mutated to serine, threonine, or glutamate. Variants with thesesingle point mutations were expressed as Fabs in HEK293 cells andinitially screened with a single cycle kinetics method on a BiacoreT100. Selected variants were also scaled up and purified for aconventional multi-cycle kinetics method. For single cycle kinetics,Biacore Series S CM5 sensor chips were immobilized with anti-human Fabantibodies (Human Fab capture kit, GE Healthcare).

Each Fab was captured from culture supernatant and the increasingconcentrations (ranging from 3 nM to 250 nM in HBSP buffer) of humanCD3εγ were injected sequentially at a flow rate of 30 μl/min in a singleanalysis cycle without regeneration of the surface in betweeninjections; 10 min dissociation was acquired for each cycle. Forconventional multi-cycle kinetics, human CD3εγ, cyno CD3εγ, or a 27-merpeptide were immobilized on Biacore Series S CM5 sensor chip using theamine coupling kit from Biacore. Serial 3-fold dilutions of each Fabvariant were injected at a flow rate of 30 μl/min. Each sample wasanalyzed with a protocol of 3-minute association and 3-minutedissociation. In both methods, the Biacore chips were regenerated using10 mM Glycine (pH 1.7). Binding response was corrected by blanksubtraction and a 1:1 Languir model of simultaneous fitting of k_(on)and k_(off) was used for kinetics analysis. The effects of thesemutations, summarized in FIG. 12 , indicate light chain residue R96 andheavy chain residues Y97, R99 and F100b play critical roles in thebinding to CD3εγ.

D. CD3 Epitope Mapping

Alanine mutations were introduced into CD3ε¹⁻²⁷-Fc in order to evaluateepitope recognition of N-terminal binding anti-CD3ε antibodies. EachCD3ε¹⁻²⁷-Fc variant was immobilized on Nunc Maxisorp plates overnight inPBS at 2 μg/ml at 4° C. After blocking the plates with 2% powdered milkin PBS containing 0.05% Tween 20 for 1 h, 100 μl of 3 nM anti-CD3ε wasadded to each well and allowed to bind for 1 h at 25° C. After 6washings with PBS containing 0.05% Tween 20, antibody binding wasdetected by the addition of anti-mouse IgG-HRP secondary antibody, asdepicted in FIG. 13A.

CD3εγ was sub-cloned into an M13 phagemid which contains a C-terminal gDtag followed by an amber stop codon so that it could be displayed onphage or expressed in a non suppressor strain of E. coli. This CD3εγphagemid was used as a template for making single alanine mutations inCD3ε by Kunkel mutagenesis. Each CD3ε alanine mutant displayed on phage,was confirmed by DNA sequencing, isolated from a single colony, grownovernight in 2YT/Carb plus KO7 helper phage and purified by PEGprecipitation. The effect of alanine mutation in CD3εγ on anti-CD3antibody binding was assessed using a phage ELISA. Each anti-CD3antibody was immobilized on a NUNC maxisorp plate at 2 μg/ml in PBSbuffer overnight at 4° C. Purified phage supernatant displaying a CD3εγalanine variant (1.0 OD₄₅₀) was added to the plate and allowed to bindat room temperature with shaking for 1 h. After washing, bound phage wasdetected with anti-M13-HRP (GE Healthcare cat #45-001-419). Binding ofeach CD3εγ alanine variant was compared to wild-type CD3εγ phage binding(FIG. 13B). Alanine variants that impacted anti-CD3 antibody binding,were further characterized by assessing binding as a function of phageconcentration (FIG. 13C).

To quantify the impact of alanine mutations in CD3 on antibody binding,selected CD3 alanine mutants were expressed in a non-supressor strain ofE. coli. The secreted CD3εγ variants were captured from the crudeperiplasmic fraction using anti-CD3 antibody UCHT1v9. UCHT1v9 wasimmobilized on a CM5 serios S chip through amine coupling using theanti-human IgG (Fc) antibody capture kit (BR-1008-39) from GEHealthcare. SPR measurements were performed on the Biacore 4000instrument, utilizing kinetic evaluation software. In order to measuremonovalent binding affinities, anti-CD3 bispecific antibodies were usedin which one arm was the anti-CD3 to be tested and the arm recognized anirrelevant antigen. The bispecific anti-CD3 antibodies were passed overthe captured supernatant in a concentration series of two-fold dilutionsfrom 0.39 to 100 nM. The resulting kinetics (FIG. 13D) were measured andcalculated using Biacore 4000 BIAevaluation software (product code28-9664-57).

E. Structural Mapping of CD3ε Binding Site

1. Hu38E4.v1 Fab

Hu38E4.v1 Fab, dissolved in 0.15 M NaCl, 25 mM tris, pH 7.5 at 10 mg/ml,and a 2-fold molar excess (1 mg) of CD3ε peptide, QDGNEEMGGITQTPYK (SEQID NO: 284) (FIG. 14A), were mixed and subjected to crystallizationtrials. Initial screening was done with a sparse matrix of precipitantsin a sitting drop vapor diffusion format. Optimized crystals grew from a1:1 mixture with reservoir solution containing 70% v/vmethyl-pentanediol, and 0.1 M HEPES buffer at pH 7.5. The reservoir wasused as a cryoprotectant. The crystals were transferred to cryogenictemperature by sudden immersion into liquid nitrogen.

The diffraction data for hu38E4.v1 Fab and CD3ε peptide co-crystal werecollected at Advanced Photon Source beam line 221D, using a MAR300 CCDdetector. The recorded diffractions were then integrated and scaledusing the program HKL2000.

The structure was phased by molecular replacement (MR) method usingprogram Phaser. The MR search model was a Fab subunit derived from acrystal structure of HGFA/Fab complex (PDB code: 2R0L). The CD3ε peptidewas built into the structure based on a Fo-Fc map. The structure wassubsequently refined with programs REFMAC5 and PHENIX using the maximumlikelihood target functions, anisotropic individual B-factor refinementmethod, and TLS refinement method, to achieve convergence. The data andrefinement statistics are show in Table 3A.

TABLE 3A Data Collection and Refinement Statistics for hu38E4.v1/CD3εComplex Space group P3221 Unit cell a = 73.2 Å, b = 73.2 Å, c = 183.7 Åα = 90° β = 120° γ = 90° Resolution 50.0-1.95 Å Total number of 42632(4188)¹ reflections Completeness (%) 100 (100) Redundancy 19.7 (8.3) I/σ7.1 (3.0) Rsym² 0.112 (0.812) Resolution range 50-1.95 Å Rcryst³/Rfree⁴0.152/0.185 Non-hydrogen atoms 3960 Water molecules 446 Average B,Overall 21.97 Average B, Protein 20.63 Average B, Water 32.27 r.m.s.d.bond lengths 0.009 Å r.m.s.d. angles 1.258° ¹Values in parentheses forare of the highest resolution shell which is 2.02 Å-1.95 Å. ²Rsym =Σ|I_(hi) − I_(h)|/ΣI_(hi) , where I_(hi) is the scaled intensity of theith symmetry-related observation of reflection h and I_(h) is the meanvalue. ³Rcryst = Σ _(h)|F_(o, h) − F_(c, h)|/Σ _(h)F_(o, h,) whereF_(o, h) and F_(c, h) are the observed and calculated structure factoramplitudes for reflection h. ⁴Value of R_(free) is calculated for 5%randomly chosen reflections not included in the refinement.

The crystal structure of the hu38E4.v1 Fab/CD3ε peptide complex wasdetermined at 1.9 Å resolution. The structure revealed that the CD3εpeptide makes a small turn and inserts deeply into the cleft betweenheavy and light chains of the 38E4.v1 Fab (FIGS. 14B and 14C). Bindingburies 666 Å² of solvent accessible surface area between the peptide andthe Fab fragment and involves an intricate network of hydrophobic,hydrogen binding and ionic interactions (FIG. 14D). The N-terminalpyroglutamate (pyroglu) ring packs against heavy chain Tyr33 and makes ahydrogen bond with heavy chain His35 in HVR-H1. The bulky side chain ofresidue F100b in HVR-H3 pushes His35 into a proper orientation for itsinteraction with pyroglu and explains the loss of binding observed whenF100b is mutated to alanine, a small side chain residue. In addition,consistent with the alanine scanning results, R96 in CDR-L3 makes acritical hydrogen bond with the carboxyl group in the pyroglu, whereasY97 in CDR-H3 makes a hydrogen bond with Met7 of the CD3ε peptide (FIG.14E). Interestingly, while alanine substitution at R99 in CDR-H3 has adramatic effect on antigen binding, the structure reveals that this sidechain points away from the CD3ε peptide and does not involve in anyinteractions with the peptide. Instead, R99 makes extensive contactswith several residues in CDR-H3, including a hydrogen bond with D101 andhydrophobic packing against Y100a that further impacts the vernierresidue, LC Y49 (FIG. 14F). These interactions are likely important forthe support and overall arrangement of CDR loops in the 38E4.v1 Fab byorganizing the critical central cleft between heavy and light chains toenable CD3ε peptide binding.

FIG. 14G identifies all residues of the 38E4.v1 Fab that were determinedto reside within 5 Å from the CD3ε peptide. These antigen contactresidues are identical between hu38E4.v1 and hu40G5c, except thatresidue G96 of hu38E4.v1 is a serine residue (S96) in hu40G5 (see FIG.14H, which depicts the location of contact residue G96 of hu38E4.v1).

The contacts between anti-CD3 (38E4.v1) and the CD3_(εγ) peptide werecalculated based on alanine scanning. The epitopes recognized by the38E4v1 anti-CD3 are contacts with a distance of 3.5 Angstroms orshorter, as provided in FIG. 109 . From this analysis, the CD3 epitopesGln1 (PCA1, pyroglutamic acid), Asp2, Glu6, and Met7 were found to beimportant contact forming residues with the paratopes of the light chainand heavy chain variable regions of the CD3 antibody.

2. SP34v52 Fab

SP34v52 Fab was dissolved in 0.25 M NaCl, 25 mM MES pH 5.5 at 10 mg/mL.The initial crystallization screening was done with a sparse matrix(PEGII, Qiagen) screen in a sitting drop vapor diffusion format. Acrystallization hit was found in a drop with the reservoir containing0.2M CaCl₂, 0.1M HEPES pH 7.5, and 30% w/v PEG 4000. Optimized crystalsgrew from a mixture of 2 μL protein and 2 μL of reservoir solutioncontaining 20-23% w/v PEG 3350, 0.1M HEPES pH 7.2, 0.1M CaCl₂. Hangingdrop vapor diffusion method was used and the final crystallization dropwas incubated at 18° C.

The diffraction data for SP34v52 Fab were collected at StanfordSynchrotron Light Source beam line 12-2, using a PILATUS detector. Therecorded diffractions were then integrated using program XDS and scaledusing the program SCALA. The structure was phased by molecularreplacement (MR) method using program Phaser. The MR search model was aFab subunit derived from a crystal structure of HGFA/Fab complex (PDBCode: 2R0L). The CD3ε peptide was build into the structure based on aF_(o)-F_(c) map. The structure was subsequently refined with programsREFMAC5 and PHENIX using the maximum likelihood target functions,anisotropic individual B-factor refinement method, and TLS refinementmethod, to achieve convergence. The data and refinement statistics areshown in Table 4 below.

TABLE 4 Data Collection and Refinement Statistics for SP34v52 Spacegroup P622 Unit cell a = b = 146.3 Å, c = 80.1 Å α = 90° β = 90° γ =120° Resolution 50.0-2.50 Å Total number of 18004 (170)¹ reflectionsCompleteness (%) 100 (100) Redundancy 19.3 (19.7) I/σ 24.0 (3.6) Rsym²0.127 (0.896) Resolution range 50-2.50 Å Rcryst³/Rfree⁴ 0.152/0.185Non-hydrogen atoms 3451 Water molecules 123 Average B, Overall 29.59Average B, Protein 29.81 Average B, Water 22.47 r.m.s.d. bond lengths0.007 Å r.m.s.d. angles 1.163° ¹Values in parentheses for are of thehighest resolution shell which is 2.51 Å-2.50 Å. ²Rsym = Σ|I_(hi) −I_(h)|/ΣI_(hi), where I_(hi) is the scaled intensity of the ithsymmetry-related observation of reflection h and I_(h) is the meanvalue. ³Rcryst = Σ _(h)|F_(o, h) − F_(c, h)|/Σ_(h)F_(o, h,) whereF_(o, h) and F_(c, h) are the observed and calculated structure factoramplitudes for reflection h. ⁴Value of R_(free) is calculated for 5%randomly chosen reflections not included in the refinement.

In FIGS. 14I-14L, the crystal structures of the hu38E4.v1 and SP34v52Fabs were compared in the same orientation. When the CD3ε peptide wassuperimposed on the SP34v52 Fab with the same orientation as in thehu38E4.v1, clear clashes of the peptide with SP34v52 were observed (FIG.14L). HVR-H2 residues R50 and R52 of SP34v52, which were not present ineither hu38E4.v1 or hu40G5c, were found to be important for the bindingof CD3 by SP34v52 (FIG. 14L). These data demonstrate that hu38E4.v1 andhu40G5c bind to CD3 in a manner distinct from that of SP34v52.

The crystal structure of the hu38E4.v1 in complex with the N-terminalpeptide of CD3_(εγ) is illustrated in FIGS. 14M and 14N. FIG. 14Mprovides a zoomed in view of the key intermolecular interactionsinvolved in contacting the sixth residue in CD3_(εγ). In a zoomed outview, FIG. 14N depicts a space filling model of the Fab/CD3 peptidecomplex where the fifth residue is completely pointing away from theinteraction site. The sixth residue, as shown, is involved in theinteractions with the Fab and points into the active site.

Example 2. Generation and Selection of T-Cell Dependent Bispecific (TDB)Antibodies

One approach to harness the high cytotoxic potential of T cells ineradicating tumor cells has been the use of T-cell dependent bispecific(TDB) antibodies. Encouraging clinical responses have been reported withmolecules such as B cell targeting blinatumomab, the CD19/CD3-bispecificBiTE antibody. However, the therapeutic promise of many reportedbispecific antibody modalities has been limited by liabilities includingunfavorable pharmacokinetics (PK), toxicity, and/or production issues.Accordingly, we initially generated and characterized anti-CD3 TDBantibodies having varied combinations of anti-CD3 and anti-tumor antigen(e.g., anti-CD20, anti-FcRH5, anti-HER2, anti-LYPD1, anti-LY6E,anti-LY6G6D, anti-PMEL17, anti-CD19, anti-CD22, anti-CD33, anti-CD79A,anti-CD79B, anti-EDAR, anti-GFRA1, anti-MRP4, anti-RET, anti-Steap1,anti-TenB2) arms, produced as full-length antibodies in theknob-into-hole format. Unexpectedly, we found that particularcombinations (pairs) of anti-CD3 and anti-tumor antigen arms resulted inTDBs exhibiting favorable activity over other TDBs.

TDB antibodies were produced as full-length antibodies in theknob-into-hole format as human IgG1, as previously described (Atwell etal. J. Mol. Biol. 270: 26-35, 1997). Half antibodies were expressed ineither E. coli or Chinese hamster ovary (CHO) cells, purified by ProteinA-affinity chromatography, and the proper half antibody pairs wereannealed in vitro as described previously (Spiess et al. Nat.Biotechnol. 2013). If TDB antibody production was carried out in CHOcells, the antibody may include an aglycosylation mutation, for example,at residue N297 (e.g., N297G), such that the TDB antibody was aneffector-less variant and unable to initiate antibody-dependentcell-mediated cytotoxicity (ADCC). FIG. 15 shows a schematic overview ofCD3/CD20 TDB production.

After annealing, the CD3/CD20 TDBs were purified by HydrophobicInteraction Chromatography (HIC) and characterized by analytical gelfiltration, mass spectrometry, and polyacrylamide gel electrophoresis.The purified antibodies ran as a single peak (>99% of the signal) in gelfiltration with less than 0.2% aggregates. No homodimers were detectedby mass spectrometry. The anti-CD20 arms tested in the generation ofCD3/CD20 TDBs included 2H7v16, 2H7v114, 2H7v511, and GA101. The anti-CD3arms tested in the generation of CD3/CD20 TDBs included UCHT1v1,UCHT1v9, UCHT1vM1, 72H6, 13A3, 30A1, 41 D9a, SP34v52, 40G5c,38E4v1-38E4v9, 21B2, 125A1, and 21A9. CD3/CD20 TDBs were tested forbinding to CD3, as well as activity, as assessed by in vitro B cellkilling assays and T cell activation assays.

A. Binding Affinity

Binding affinities for the each of the CD3/CD20 TDBs were tested byBiacore or FACS analysis, as described above for the anti-CD3antibodies. Briefly, for Biacore binding assays, human CD3εγ wasimmobilized on Biacore Series S CM5 sensor chip using the amine couplingkit from Biacore and CD3/CD20 TDBs or Fab variants thereof were in theflow through. For FACS binding assays, either Bjab cells (for B cellantigens) or Jurkat cells (for CD3 antigen) were incubated with variousconcentrations of TDB antibodies at 4° C. for 30 minutes, then cellswere washed and incubated with 2^(nd) antibody (anti-huIgG-PE; BDBioscience) for another 15 minutes, before cells were washed again andready for FACS analysis. FIG. 16 shows the results of in vitro FACSbinding assays of CD3/CD20 TDBs. The results demonstrate that particularcombinations of anti-CD3 antibody arm and anti-tumor antigen arm (e.g.,anti-CD20 arm) result in TDB antibodies with more favorable bindingproperties. FIG. 17 shows the monovalent and bivalent binding affinitiesfor these particular CD3/CD20 TDBs. The particular pairing of 2H7v16with anti-CD3 arms (e.g., UCHT1v9), for example, resulted in a CD3/CD20TDB that displayed unexpectedly strong binding to both Bjab and Jurkatcells compared to the other tested CD3/CD20 TDBs having differentanti-CD20 arms. The binding affinity of other CD3/CD20 TDBs having a2H7v16 anti-CD20 arm and various anti-CD3 arms were also tested (seeFIGS. 18-24 ).

B. In Vitro B Cell Killing and T Cell Activation Assays

The generated CD3/CD20 TDBs were also tested for their ability tosupport B cell killing and the activation of the cytotoxic effect of Tcells. In these assays, B tumor cell lines (Bjab) were obtained fromATCC, and PBMCs were isolated from whole blood of healthy donors byFicoll separation. If needed CD4+ T and CD8+ T cells were separated withMiltenyi kits according to manufacturer's instructions. Cells werecultured in RPMI1640 supplemented with 10% FBS (Sigma-Aldrich) at 37° C.in a humidified standard cell culture incubator. For Bjab cell killingassays, 20,000 Bjab cells were incubated with effector cells either ashuPBMCs or purified T cells as indicated ratios per assay, in thepresence of various concentrations of TDB antibodies for a time periodas indicated per assay. For endogenous B cell killing assays, 200,000huPBMCs were incubated with various concentrations of TDB antibodies forhours indicated per assay. At the end of each assay, live B cells weregated out as PI-CD19+ or PI-CD20+ B cells by FACS, and absolute cellcount was obtained with FITC beads added to reaction mix as internalcounting control. % of cell killing was calculated based on non-TDBtreated controls. Activated T cells were detected by CD69 and CD25surface expression.

The varied efficacies of the generated TDB antibodies with bispecificityfor CD3 and a second biological molecule (in this instance, CD20),underscore the critical and unpredictable contributions of both antibodyarms in the generation of an exemplary TDB possessing high efficacy (seeFIGS. 25-49 ).

Example 3. Characterization of Exemplary CD3/CD20 TDBs (CD20 TDBs)

We further characterized two of the exemplary CD3/CD20 TDBs (CD20 TDBs)described above, which showed high efficacy in the in vitro B cellkilling and T cell activation assays. The CD20 arm of each TDB antibodywas anti-CD20 clone 2H7.v16 (see FIG. 50 ), while the CD3 arm was cloneUCHT1v9 (see, e.g., Zhu et al. Int. J. Cancer. 62: 319-324, 1995) orcyno cross-reactive clone 40G5c (see, e.g., FIG. 51 ), which sharescomparable activities.

Materials and Methods

A. Antibody Production

T-cell dependent bispecific (TDB) antibodies were produced asfull-length antibodies in the knob-into-hole format as human IgG1 aspreviously described (Atwell et al. J. Mol. Biol. 270: 26-35, 1997).Half antibodies were expressed in E. coli and thus aglycosylated,purified by Protein A-affinity chromatography, and the proper halfantibody pairs were annealed in vitro as described previously (Spiess etal. Nat. Biotechnol. 2013). After annealing, the antibodies werepurified by Hydrophobic Interaction Chromatography (HIC) andcharacterized by analytical gel filtration, mass spectrometry, andpolyacrylamide gel electrophoresis. The purified antibodies ran as asingle peak (>99% of the signal) in gel filtration with no detectableaggregates (FIG. 52A), and no homodimers were detected by massspectrometry (FIG. 52B).

B. In Vitro B Cell Killing and T Cell Activation Assays

B tumor cell lines are obtained from ATCC, and PBMCs were isolated fromwhole blood of healthy donors by Ficoll separation. CD4+ T and CD8+ Tcells were separated with Miltenyi kits according to manufacturer'sinstructions. Cells were cultured in RPMI1640 supplemented with 10% FBS(Sigma-Aldrich). For B cell killing assays, live B cells were gated outas PI-CD19+ B cells by FACS, and absolute cell count was obtained withFITC beads added to reaction mix as internal counting control. ActivatedT cells were detected by CD69 and CD25 surface expression. IntracellularGranzyme B induction was detected by FACS. Perforin concentration inmedia is detected by ELISA (eBioscience). All antibodies were purchasedfrom BD Bioscience.

C. In Vivo Efficacy Studies in Murine Models

Humanized NSG and SCID mice were purchased from Jackson Labs. Human CD20transgenic mice and human CD3 transgenic mice were produced aspreviously described (Gong et al. J. Immunol. 174: 817-826, 2005 and dela Here et al. J. Exp. Med. 173: 7-17, 1991), and human CD20/CD3 doubletransgenic mice were produced by crossing the two single transgenicmice. Human lymphoma mouse models were generated by injecting 5×10⁶Bjab-luciferase cells alone or mixed with 10×10⁶ human donor PBMCs inHBSS subcutaneously into the right flanks of 40 female mice. Mice weretreated intravenously with vehicle or 0.5 mg/kg CD20 TDB one hourpost-inoculation and one week following the initial treatment. Tumorswere measured 1-2 times per week, and body weights were measured twiceper week up to 7 days following the final treatment. If no weight losswas observed, weights were no longer taken for a given animal. If weightloss was greater than 15% of the total body weight, affected mice wereweighed daily, and euthanized (or brought to the attention of theveterinary staff) if weight loss exceeded 20%. Clinical observationswere performed twice per week throughout the duration of the study tomonitor the health of the animals; any animal with a tumor of a size orcondition that may interfere with the health or activity of the animalwas euthanized. Otherwise, animals were euthanized 6 months after theinitial treatment or if the tumor became ulcerated or its volumeexceeded 2500 mm³.

Patient-derived chronic lymphocytic leukemia (CLL) mouse models weregenerated as previously described (Bagnara et al. Blood. 117: 5463-5472,2011). Briefly, 5×10⁵ activated T cells were purified from CLL PBMCs andinjected retro-orbitally into NSG mice. Following T cell engraftment,2×10⁷ CLL PBMCs were injected retro-orbitally. After 14 days,circulation of transplanted B and T cells was confirmed by FACSanalysis. Successfully engrafted animals were subsequently treated 3.5weeks later with TDB antibodies administered intravenously by tail veininjection. Animals were euthanized 6 or 14 days after treatment. Wholeblood was collected by puncture of the retro-orbital sinus usingheparinized pipets and immediately transferred into heparinized tubes,while the animals were under anesthesia, or by terminal cardiacpuncture, with a heparinized syringe after CO2 euthanasia. Spleens werecollected after CO2 euthanasia. For every study, clinical observationswere performed twice per week to monitor the health of the animals.Animal body weights were taken at least once a week. PBMCs were isolatedafter red blood cell lysis, and analyzed by FACS for B cells(muCD45+CD19+) and T cells (muCD90.2+CD4+, or muCD90.2+CD8+). Allantibodies used are purchased from either BD Biosciences oreBiosciences.

D. PKPD Study in Cynomolgus Monkeys

All cynomolgus monkey studies were conducted using purpose bred, naïve,cynomolgus monkeys of Chinese origin. For the single dose PKPD study, 3male cynomolgus monkeys were administered a single slow bolus IV dose of1 mg/kg of CD20 TDB; for the repeat dose study, 4 cynomolgus monkeyswere administered an IV slow bolus dose of 1 mg/kg of CD20 TDB onceweekly for a total of 4 dose. Whole blood or tissues was collected atselected time points for B cell and T cell count by FACS. Serum wascollected, and stored at −70 C until assayed using an ELISA to determinethe amount of test article in each serum sample. Serumconcentration-time profiles from each animal were used to estimatepharmacokinetic (PK) parameters using WinNonlin software (Pharsight;Mountain View, Calif.).

High Quality CD20 TDB Produced as a Full Length, Humanized IgG withConventional Antibody PK Property

To explore targeting properties that could affect B-cell targeting TDBpotency including antigen identity, size of the extracellular domain,and epitope distance from the membrane, we created over 40 differentTDBs targeting epitopes on CD3_(ε), CD19, CD20, CD22, CD79a, and CD79b.Representative results are shown in FIG. 56I. We found that the mostpotent TDBs were those that targeted cancer target antigens with smallextracellular domains (ECDs) and epitopes close to the target cellmembrane. Among the best targets were CD20, CD79a, and CD79b withpotencies around 10 ng/ml or 67 pM for killing of normal donor B cellsby autologous T cells.

Anti-CD20/CD3 TDB (CD20-TDB) is described here as a proof of conceptmolecule showcasing the pharmacological activity of these B-celltargeting TDBs. CD20 TDBs were produced as full-length, fully humanizedIgGs with natural antibody architecture from bacteria, free ofhomodimers and aggregates (FIG. 52 ). The pharmacokinetic (PK) propertyof CD20 TDB in rats, a non-binding species, resembles that of otherhuman IgG antibodies, with a half-life of about 7 days (FIG. 53 ).

B Cell Killing with CD20 TDB is T Cell Dependent Via theGranzyme-Perforin Pathway

To assess CD20 TDB as a potential therapy for cell proliferativedisorders, such as CD20+ B cell malignancies, we first investigated itsmechanism of action as a T cell-recruiting bispecific antibody. Distinctfrom ADCC activity, which is the main mechanism of action for classicmonoclonal antibody therapy, CD20 TDB doesn't require the Fc region forits activity. F(ab′)2 portion of CD20 TDB retained the same potency asthe full-length IgG CD20 TDB in B cell killing (FIG. 54A). CD20 TDB is aconditional agonist, requiring target expression, T cells, and antibodyfor activity. B cell killing activity of CD20 TDB is T cell-dependent,as no B cell killing was detected with PBMCs depleted of CD3+ T cells(FIG. 54B). Target expression is required for T cell activation, as noCD20 expression results in no activated T cells (FIG. 54C). CD20 TDB isable to activate both CD4+ and CD8+ T cells as measured by the inductionof both CD69 and CD25 on T cells (FIG. 54D). Comparable B cell killingcan be achieved with either T cells as effectors, while CD8+ T cellsappear to be more potent in BJAB cell killing, as CD8+ T cells resultedin higher extent of cell killing than equal number of CD4+ T cells (FIG.54C). However, Granzyme upregulation is more prevalent within CD8+ Tcells (FIG. 54E), as well as higher levels of perforin and Granzymes Aand B (not shown) release associated with CD8+ T cells was detected inthe media by ELISA (FIG. 54F). Activated T cells are capable ofproliferation (FIG. 55 ). Overall T cell count, however, didn't increasesignificantly after 24 hours in the presence of CD20 TDB and B cellswithout cytokine supplement in vitro, likely due to culture conditions.Robust T cell expansion was indeed observed in vivo from efficacystudies with murine models and in cynomolgus monkeys (FIGS. 58A and67C).

CD20 TDB Potent in Killing B Leukemia/Lymphoma Cells, and in AutologousB Cell Killing In Vitro B cell killing potency of CD20 TDB was alsotested with more than a dozen B leukemia/lymphoma cell lines in vitro.To assess the potency of the CD20-TDB, 8 lines were selected thatrepresent cells with a wide range of CD20 expression level (FIG. 56B).The dose-response B cell killing curves are shown with the 8 cell lines,with PBMC isolated from healthy donor as effector cells (FIG. 56A).Significantly, CD20-TDB had no activity against SU-DHL1 cells that aredevoid of CD20 expression. The potency of the CD20-TDB was somewhatcorrelated with the various levels of surface CD20 detected by flowcytometry (56A). Nonetheless, CD20 TDB is potent in killing all 8 linesin a dose-dependent manner, with EC50 ranging from 0.38 to 11 ng/ml for24 hour assay. The extent of cell killing varies somehow from 60 to 90%with up to 1000 ng/ml TDB in a 24 hour assay (FIG. 56C). In general,complete B cell killing can be achieved with higher antibodyconcentration or extended assay time. SU-DHL-1 cells are included in thekilling assay as a CD20 negative control, where no cell killing isobserved demonstrating the requirement for target expression for CD20TDB activity. Activity of CD20 TDB appears to require very low level oftarget expression, as Nalm-6 and SC-1 cells shown here all have very lowCD20 surface expression (FIG. 56B). Monovalent binding affinity of CD20TDB for CD20 is weaker than bivalent binding affinity of the parentalanti-CD20, with a KD of 54 nM determined by scatchard. Taken together,the K_(D) value and CD20 TDB B cell killing potency, receptor occupancyrequired for CD20 TDB activity is only less than 0.1%. TDBs generated totarget different B cell antigens are also effective in mediating B cellkilling as shown in FIG. 56D, where TDBs targeting 5 different B cellantigens, including a CD20 TDB (TDB A: 2H7v16/UCHT1v9), killed 75% to90% of B cells. CD20 TDB can further mediate the killing of additional Blymphoma lines with variable CD20 surface antigen expression (FIG. 56E).

CD20 TDB is also highly potent in autologous B cell killing, tested withhuman PBMCs isolated from peripheral blood of healthy donors (FIG. 56F).Shown in FIG. 56F are the dose-responsive killing curves for 8 randomdonors, as well as a summary plot for EC50 and extent of B cell killing(FIG. 56G) with 1000 ng/ml antibody in a 24 hour assay for 30 donors.Out of the 30 samples tested, 57 to 96% of B cells were killed with upto 1000 ng/ml antibody within 24 hours, with EC50 ranging from 0.43 to135 ng/ml with a median value of less than 3 ng/ml. The extent of B cellkilling within 24 hours by CD20 TDB is very comparable or higher than Bcell killing by an anti-CD3/anti-CD19 scFv (FIG. 56H).

CD20 TDB is Potent in Depleting B Cells In Vivo in Murine Models

As our tested CD20 TDB does not recognize murine CD20 and CD3 antigens,we took advantage of human CD20 and human CD3 transgenic mice (describedabove) to produce human CD3/CD20 double transgenic mice for subsequentefficacy studies in vivo. As shown in FIG. 57A, human CD3/CD20 doubletransgenic mice express huCD3ε on the surface of CD4+ and CD8+ T cellsin addition to huCD20 on the surface of CD19+ B cells at detectablelevels compared to human derived T and B cells. With human CD20transgenic mice, only rituximab is able to deplete B cells, as CD20 TDBcannot engage murine T cells without human CD3 expression (FIG. 57B).While with human CD3/CD20 double transgenic mice, CD20 TDB is able toengage murine T cells expressing huCD3, and is potent in depletingmurine B cells expressing huCD20 (FIG. 57C). CD20 TDB appears to be morepotent in depleting B cells in vivo, as fewer B cells are detected inmouse spleens 7 days after a single IV dose of CD20 TDB at 0.5 mg/kg,compared to after a single dose of rituximab at 10 mg/kg. A HER2 TDB,which has the same CD3 arm while with the other arm binds to HER2, wasused as an isotype control here, and showed no activity here in celldepletion.

To explore the lowest efficacious dose for CD20 TDB in depleting B cellswith human CD3/CD20 double transgenic mice, mice were treated with asingle dose of CD20 TDB starting at 0.5 mg/kg down to 0.00005 mg/kg.Then B cell count in blood was monitored on D1 (24 hours after dose),D8, and D15. Decreased B cell count was observed on D1, and B celldepletion was sustained up to D15 following CD20 TDB treatment (FIG.58A). Consistent with this observation of B cell count in blood, nearcomplete B cell depletion in mouse spleens was achieved at D7 after asingle dose of 0.5 mg/kg, while a lower dose of 0.05 mg/kg resulted inspleen B cell depletion partially and approximated an ED50 dose level(FIG. 58B). A time-course study with the double transgenic mice revealedthat B cell depletion is near complete in spleens as early as 3 daysafter single dose treatment at 0.5 mg/kg, without significant sign of Bcell recovery until D14 (FIG. 58A). As seen in FIG. 58C, CD20 TDBmediates B cell depletion in the periphery of double transgenichuCD20/huCD3, which is detected in the blood as early as two hours aftertreatment and maintained for up to seven days post treatment.Furthermore, activated CD8+ and CD4+ T cells are detectable in the bloodwithin two hours of CD20 TDB administration and then decline by two dayspost-treatment (FIG. 58D).

Further, CD20 TDB depleted marginal zone B cells (MZB) (FIG. 59A andFIG. 59B) as efficiently as follicular B cells (FOB) (FIG. 59A and FIG.59C) in mouse spleens, after a single IV dose of 0.5 mg/kg. We observedthat splenic B cells declined 50% from baseline by day 1 (24 hours postdose) and continued to decline rapidly to reach a nadir on day 3 thatwas maintained throughout the study. This is apparently different fromprevious report with rituximab, where microenvironment is thought toplay a role in rituximab effectiveness, suggesting different mode ofaction for CD20 TDB in vivo than that for rituximab. Murine T cellactivation is usually observed as soon as 30 minutes after CD20 TDBtreatment in blood, and mostly within the first 24 hours in spleen(FIGS. 59D and 59E). Following T cell activation, increase in T cellcount was observed around D2-D3 (FIGS. 59D and 59E), as a result of cellproliferation. By day 2 the majority of T cells were no longerCD69-positive, although levels of CD69+CD8+ cells continued to rangefrom 10-30% for the remainder of the two week study. However, possiblydue to activation induced cell death, T cell count tends to decreasefollowing the expansion phase. T cell count will recover eventuallyafter TDB treatment, suggesting no inhibitory effect of CD20 TDBtreatment in murine T cell regeneration.

Humanized NSG mice were also used to further validate CD20 TDB potencyin B cell depletion in murine models, and in a repeat dose setting. Theactual mice enrolled in the study shown in FIGS. 60A-60D had 35-80%human CD45+ cells in peripheral blood, and the range of CD4+, CD8+, andCD20+ cells were 12-25, 2.1-8.7, and 32-60% respectively (percentagereported as out of viable leukocyte gate). Representative examples ofthis baseline characterization are shown in FIG. 60E. Levels of CD3 andCD20 target antigens from these mice were compared to that of normalhuman donors and were found to be not significantly different (FIG.60F). Shown in FIG. 59 , humanized NSG mice were treated with 3 weeklydoses of CD20 TDB at 0.5 mg/kg. B cells were depleted in blood at D7,with almost no B cells detected at D21 (FIG. 60A). Robust B celldepletion was also observed in spleens of the TDB treated mice at D21(FIG. 60B). Furthermore, treatment of humanized NSG mice with CD20 TDBstimulated T cell proliferation and led to B cell depletion as shown inFIG. 60C. For CD8+ T cells, their cell counts increased up to 10-fold inblood at D7, and returned to baseline or lower at D14 and D21 (FIG.60D). Similar trend was also observed for CD4+ T cells.

CD20 TDB is Potent in Killing CLL B Cells In Vitro and In Vivo

We also tested CD20 TDB potency in killing B leukemia cells withautologous T cells from CLL patients, where B tumor burden is usuallyhigh while T cell count is low and T cell function could be potentiallycompromised (Riches et al. Semin. Cancer Biol. 20(6): 431-438, 2010).PBMCs isolated from peripheral blood of nine CLL patients were incubatedwith a single high dose of 1000 ng/mL CD20 TDB for up to 48 hours. Asshown in FIG. 61A, CD20 TDB is potent in killing CLL B cells withautologous T cells. For the 2 samples shown, B leukemia tumor burden is70% with 8.4% CD8+ T cells in PBMCs for patient sample #1, and 80% with4.4% CD8+ T cells for patient sample #2. CD20 TDB apparently can achieveefficient B cell killing with very low effector to target ratios (1:8and 1:18 with the 2 samples shown here). Killing of CLL B cells withautologous T cells by CD20 TDB is highly correlated with CD8+ T cellcount (FIG. 61B). We found T cell content varied significantly (between0.4 and 8% of mononuclear cells), and strikingly, we observed that theextent of B cell cytolysis compared to pretreatment values was highlycorrelated to T cell content. By supplementing purified CD8+ T cells toCLL PBMCs, where very few autologous T cells are available, B leukemiacells were efficiently killed by CD20 TDB in a T cell dependent manner(FIG. 61C).

CD20 TDB is also potent in depleting CLL leukemia cells engrafted inmice (FIG. 62A). In brief, NSG mice were grafted with patient leukemiacells subsequent to engraftment of patient-derived autologous activatedT cells, and treatment is initiated following confirmed establishment ofthe leukemic graft. IHC staining of representative examples of mousespleens showed successful engraftment of B leukemia cells and autologousT cells from CLL patients in NSG mice. After a single dose of CD20-TDBtreatment at 0.1 or 0.5 mg/kg, few B cells could be detected. B celldepletion was also observed with rituximab treatment, while no B celldepletion is detected with HER2-TDB as an isotype control. (FIG. 62B).

In the context of tumor progression, CD20 TDB treatment is effective inpreventing the growth of B-cell lymphoma tumors in the presence of humandonor PBMCs. SCID (severe combined immune deficiency) mice transplantedwith human Bjab cells developed detectable tumors when treated withvehicle or CD20 TDB alone by day 12 post-inoculation. Further,transplantation of PBMCs alone delayed tumor outgrowth, but these micedeveloped detectable tumors by day 25 post-inoculation. Thus, CD20 TDBis also effective in preventing tumor growth in vivo in the presence ofPBMC effector cells (FIG. 63 ).

CD20 TDB Potency Requires Very Low CD20 Expression Level

In addition to the different requirement for antibody Fc region for CD20TDB activity comparing to conventional anti-CD20, and possibly differentdependence on tumor microenvironment, CD20 TDB also appears to require alower level of antigen expression for efficient B cell killing. For Bjabcells, which have high level of CD20 expression (FIG. 64A), comparablecell killing were accomplished with rituximab and CD20 TDB (FIG. 64B).However, Nalm-6, SC-1, and OCI-Ly19 cells with much reduced level ofCD20 expression (FIG. 64A) were only killed by CD20 TDB, while no cellkilling was detected with rituximab (FIG. 64C). Estimated CD20 copynumber for these CD20-low cell lines is less than 500, based onscatchard and FACS binding data in comparison to BJAB cells (data notshown). In addition, monovalent binding affinity of CD20-TDB for CD20 is˜50-100 nM, significantly less than 1-5 nM affinity of rituximab (bothmeasured by scatchard). Taken together, the potency of CD20-TDB isconsistent with the notion that TCR triggering only requires lowreceptor occupancy of 10-100 molecules (Purbhoo, M. A., et al. NatImmunol 5:524-530, 2004; Irvine, D. J., et al. Nature 419:845-849, 2002;Sykulev, Y., et al. Immunity 4:565-571, 1996).

CD20 TDB is Active in Presence of Rituximab and Steroid

Since rituximab and its combination with chemotherapy are widely used intreating B cell malignancies in the clinic, it's important to explorehow CD20 TDB can be used within this context, as CD20 TDB and rituximabboth target the same antigen. We took advantage of rituximab-DANA, aneffector-less rituximab variant (rituximab containing substitutions ofresidues 265 and 297 to alanine (DANA mutations described in U.S. Pat.Nos. 7,332,581 and 8,219,149)), which only binds to CD20 without B cellkilling activity, as tested in human CD20/CD3 double transgenic mice(FIG. 64D). Pretreatment of normal donor B-cell target cells with thisinert rituximab molecule that competes with CD20-TDB binding had aremarkably minimal effect in blunting the activity of CD20-TDB. Atconcentrations up to 250 μg/ml rituximab-DANA (a 5000-fold excess overthe 42 ng/ml EC50 dose level), we observed only modest shifts in thedose-response curves in vitro (less than 7-fold shift at the EC50, 42versus 320 ng/ml). Remarkably, CD20 TDB is still active in this setting.Although the EC50 for CD20-TDB was increased up to ˜7-fold with higherrituximab-DANA concentration, the extent of B cell killing is notsignificantly changed, (FIG. 65A). This is consistent with our previousfindings that very low antigen expression level, or very low receptoroccupancy, is required for CD20 TDB potency. The in vitro observationswere recapitulated in vivo in CD3/CD20 dual transgenic mice which werepretreated with 2 or 10 mg/kg of the rituximab-DANA protein andsubsequently challenged with CD20-TDB. Here we show in vivo that CD20TDB is still active in depleting B cells in mice pre-treated withrituximab-DANA (FIG. 66 ). These results indicate great versatility inprospective combination therapies for B cell malignancies.

CD20 TDB is a T cell recruiting antibody, and its potency is dependenton activating T cells. It was also explored to see whether steroidpre-treatment, which could potentially impact T cell immune response,would affect CD20 TDB activity. In vitro CD20 TDB was still active inkilling B cells in the presence of high concentration of dexamethasone(FIG. 65B).

Pre-Clinical Validation of CD20 TDB as a Potential Therapy for CD20+ BCell Malignancies in Cynomolgus Monkeys

Pilot PKPD study for CD20 TDB was also conducted in cynomolgus monkeys.In a single dose study, where 3 animals were treated once intravenouslywith 1 mg/kg CD20 TDB, complete B cell depletion were observed in blood(FIG. 67A), as well as in spleens and lymph nodes (FIGS. 67B and 67C), 7days after antibody treatment. The historic vehicle controls are shownas the mean and standard deviation of 4 vehicle-treated animals (FIG.67D). No apparent T-cell loss was observed, as both CD8+ T cells andCD4+ T cells were at comparable or higher level to controls, whencalculated as % of lymphocytes. T cell activation was detected in blood4 hours after dosing. No T cell loss was observed, and apparently higherCD8+ T cell count was detected in blood 7 days after treatment (FIG.67A).

Long-term effect of CD20 TDB treatment on immune cells was also testedwith a 4-week repeat dose study followed by an 8-week recovery period.In blood from 4 treated animals with a weekly dose of 1 mg/kg, B and Tcell counts, as well as CD20 TDB serum concentration, were measured andplotted for each individual animal over 77 days (FIG. 68A). In all 4animals, B cells were not detected in blood shortly after treatment, anddidn't come back as long as CD20 TDB serum concentration remained above100 ng/ml (animal 4502 versus animals 4001, 4002, and 4503). CD8+ T cellcounts, as well as that of CD4+ T cells to a lesser extent,significantly increased after the first dose, and gradually returned towithin 25-150% of baseline values. Taken together, CD20 TDB is highlyactive in depleting B cells, without compromising T cells.

The PK property of CD20 TDB was also summarized in FIG. 68B, with CD20TDB serum concentration measured from both studies. As shown for therepeat-dose study, CD20 TDB maintained good exposure throughout, with CLat about 17 ml/day/kg during the first dose (D0-D7). Target mediatedclearance appears to be higher during the first dose (D0-D7), as CLvalue decreased to about 6 ml/day/kg during the fourth dose (D21-28).

Combination of CD20 TDB with PD-L1 Antagonist in a Syngeneic Tumor Model

In vivo efficacy of a CD20 TDB in combination with a PD-L1 antagonist (amurine IgG2a isotype anti-PD-L1 antibody, 25A1, with DANA mutations) ina syngeneic tumor model was also tested. In this study, A20-huCD20 mouseB lymphoma cells which express human CD20 and mouse PD-L1 on their cellsurface were utilized for generating a syngeneic tumor model (see, e.g.,FIG. 69A). The CD20 TDB used was a murine IgG2a isotype 2H7v16/2C11 TDBproduced in knob-in-hole (K&H) format (see, e.g., Atwell et al., J MolBiol., 270:26-35, 1997), wherein the “knob” arm is anti-CD20 2H7v16 andthe “hole” arm is anti-CD3 2C11 (Leo et al., Proc Natl Acad Sci USA,84:1374-8, 1987). The PD-L1 antagonist used was a murine IgG2a isotypeanti-PD-L1 antibody with DANA Fc mutations (substitution of residues 265and 297 to alanine; see, e.g., U.S. Pat. Nos. 7,332,581 and 8,219,149).

On Day −7, 65 Balb/C mice were inoculated subcutaneously into the rightunilateral-thoracic area with 2.5 million A20pRK-CD20-GFP cells in HBSSin a volume of 100 μl (not to exceed 200 μl). The mice were allowed togrow tumors. The mice were then weighed and measured 1-2 times per weekuntil tumors achieved a mean tumor volume of approximately 100-200 mm³(approximately 7 days after inoculation). The animals were then dividedinto the following four treatment groups: Group 1: 2.5 million A20/CD20,Vehicle, qwx3, IV, n=9; Group 2: 2.5 million A20/CD20, anti-CD20xCD3 K&HTDB (2H7v16-2C11 murine IgG2), 0.5 mg/kg, qwx3, IV, n=9; Group 3: 2.5million A20/CD20, aPDL1 (25A1, mIgG2a DANA), 10 mg/kg, tiwx3, IP, n=9;and Group 4: 2.5 million A20/CD20, aPDL1 (25A1, mIgG2a DANA), 10 mg/kg,tiwx3, IP+anti-CD20xCD3 K&H TDB (2H7-2C11 murine IgG2), 0.5 mg/kg, qwx3,IV, n=9. Mice not recruited into one of the above treatment groups dueto dissimilar tumor volume were euthanized. Treatment began on Day 0,and all antibody dosing was conducted intravenously in a volume of 100ml as described above.

Tumors were measured 1-2 times per week. Body weights were measured twotimes per week up to 7 days after the final treatment. If no weight losswas observed, weights were no longer taken. If weight loss was observedto be >15%, affected mice were weighed daily and euthanized if weightloss was greater than or equal to 20%. For the entire study, clinicalobservations were performed twice per week to monitor the health of theanimals, and any animal with a tumor which was of a size or conditionthat may interfere with the health or activity of the animal was beeuthanized.

As depicted in FIG. 69B, the combined treatment of CD20 TDB withanti-PD-L1 antibody (Group 4) exhibited an unexpected and synergisticeffect in inhibiting tumor growth when compared to treatment with CD20TDB, anti-PD-L1 antibody, or vehicle alone.

Combination of CD20 TDB with PD-1 Antagonist in a Syngeneic Tumor Model

Additionally, the in vivo efficacy of a CD20 TDB in combination with aPD-1 antagonist (a murine IgG2 isotype anti-PD1 antibody, 8F11, withDANA mutations) was also tested in the A20/huCD20 syngenic B lymphomamouse model. In this study, the CD20 TDB used was a murine IgG2a isotype2H7v16/2C11 TDB, and the PD-1 antagonist used was a murine IgG2 isotypeanti-PD-1 antibody with DANA Fc mutations.

A20 mouse B lymphoma cells were transfected to express human CD20 andGFP and subsequently single cell sorted for clonal selection andexpansion for implantation. Female Balb/c mice (Charles River;Hollister, Calif.) 8-10 weeks old were inoculated subcutaneously in theright unilateral thoracic region with 2.5 million A20.hCD20-GFP cells.When tumors reached a mean tumor volume of 100-200 mm³, mice wererecruited and randomized into one of four treatment groups (n=9mice/group) and antibody treatment started on the following day 1: Group1 (2.5 million A20/CD20, vehicle, qwx3, IV); Group 2 (2.5 millionA20/CD20, anti-CD20xCD3 K&H TDB (2H7v16-2C11 murine IgG2), 0.5 mg/kg,qwx3, IV); Group 3 (2.5 million A20/CD20, anti-PD1 (8F11, mIgG2a DANA),10 mg/kg, tiwx3, IP); and Group 4 (2.5 million A20/CD20, anti-PD1 (8F11,mIgG2a DANA), 10 mg/kg, tiwx3, IP+anti-CD20xCD3 K&H TDB (2H7v16-2C11murine IgG2), 0.5 mg/kg, qwx3, IV).

The mice were treated with vehicle or CD20 TDB at 0.5 mg/kg weekly IVfor 3 weeks, and/or anti-PD-1 antibody at 10 mg/kg IV for the firstdose, followed by IP dosing 3 times a week for 3 weeks. (N=9 mice/group)

As depicted in FIGS. 108A and 108B, the combined treatment of CD20 TDBwith anti-PD-1 antibody (Group 4) exhibited an unexpected andsynergistic effect in inhibiting tumor growth when compared to treatmentwith CD20 TDB, anti-PD-1 antibody, or vehicle alone.

Example 4. Generation and Characterization of Exemplary CD3/FcRH5 TDBs(FcRH5 TDBs)

We also explored the capacity of TDB antibodies to recruit the cytotoxicactivities of T cells in eradicating tumor cells by recognition of adifferent cell surface antigen, FcRH5. To this end, we generated andcharacterized bispecific anti-CD3 antibodies having an anti-CD3 arm andan anti-FcRH5 arm (FcRH5 TDBs). As described above, the FcRH5 TDBs wereproduced as full-length antibodies in the knob-into-hole format as humanIgG1, as previously described (Atwell et al. J. Mol. Biol. 270: 26-35,1997). Half antibodies were expressed in E. coli, purified by ProteinA-affinity chromatography, and the proper half antibody pairs wereannealed in vitro as described previously (Spiess et al. Nat.Biotechnol. 2013). After annealing, the FcRH5 TDBs were purified byHydrophobic Interaction Chromatography (HIC) and characterized byanalytical gel filtration, mass spectrometry, and polyacrylamide gelelectrophoresis, as described above. The anti-FcRH5 arm used in thegeneration of FcRH5 TDBs was that of anti-FcRH5 antibody 1G7, comprising(a) a VH domain comprising an amino acid sequence of SEQ ID NO: 268 and(b) a VL domain comprising an amino acid sequence of SEQ ID NO: 269. Theanti-CD3 arms tested in the generation of FcRH5 TDBs included UCHT1v9,40G5c, and 38E4v1.

The specific FcRH5 TDBs were tested for binding to CD8+ T cells (CD3binding), as well as activity, as assessed by in vitro cytotoxicityassays and T cell activation assays.

A. Binding Affinity

Binding affinities for the each of the FcRH5 TDBs were tested FACSanalysis, as described above for the CD20 TDBs. Briefly, for FACSbinding assays, CD8+ T cells were incubated with various concentrationsof FcRH5 TDB antibodies at 4° C. for 30 minutes, then cells were washedand incubated with 2^(nd) antibody (anti-huIgG-PE; BD Bioscience) foranother 15 minutes, before cells were washed again and ready for FACSanalysis. FIG. 70 shows the results of in vitro FACS binding assays ofFcRH5 TDBs. The results demonstrate that the particular combination ofanti-CD3 antibody arm, 38E4v1, pair with the anti-FcRH5 arm, 1G7, resultin an FcRH5 antibody with higher binding affinity for effector cells.

B. In Vitro MOLP-2 Target Cell Killing and T Cell Activation Assays

The generated FcRH5 TDBs were also tested for their ability to supportkilling of FcRH5-expressing MOLP-2 target cells and the activation ofthe cytotoxic effect of T cells. In vitro cytotoxicity was monitored byflow cytometery. Target cells were labeled with CFSE according tomanufacturer's protocol (Invitrogen, #C34554). The carboxyfluoresceinsuccinimidyl ester (CFSE)-labeled target cells and purified CD8+ T cellsfrom human PBMC were mixed in a 3:1 ratio, with or without TDB for 48hours. The cells were resuspended in equal volume of PBS+2% FBS+1 mMEDTA+propidium iodine (PI). Flow cytometry analysis was done on aFACSCalibur in automation format. The number of live target cells wascounted by gating on CFSE+/PI negative cells. The percentage ofcytotoxicity was calculated as follows: % cytotoxicity (live target cellnumber w/o TDB—live target cell number w/TDB)/(live target cell numberw/o TDB)×100. As depicted in FIGS. 71A and 71B, FcRH5 TDBs with UCHT1v9or 38E4v1 for their anti-CD3 arm showed robust in vitro MOLP-2 targetcell killing compared to the FcRH5 TDB having 40G5c as its anti-CD3 arm.

When tested for T cell activation assays, FIGS. 72A-72D show that FcRH5TDBs with UCHT1v9 or 38E4v1 for their anti-CD3 arm were capable ofrobustly inducing T cell activity in vitro, compared to the FcRH5 TDBhaving 40G5c as its anti-CD3 arm. In these assays, target cells andpurified CD8+ T cells were mixed in the presence or absence of TDB and Tcell activation was analyzed by flow cytometry. At the end of theincubation, cells were stained with CD8-FITC (BD Bioscience, 555634)CD69-PE (BD Bioscience, 555531) and CD107a-Alexa-Fluor647 (eBioscience,51-1079). Alternatively, after surface stained with CD8-FITC andCD69-PE, cells were fixed and permeabilized with Cytofix/CytoPermsolution (BD Bioscience, 554722) and intracellular stained withanti-granzyme B-Alexa-Fluor647 (BD Bioscience, 560212). The T cellactivation was evaluated by the percentage of CD8+CD69+, CD8+CD107a+,and CD8+CD69+GranzymeB+ cells.

Example 5. Generation and Characterization of Exemplary CD3/HER2 TDBs(HER2 TDBs)

We also explored the capacity of TDB antibodies to recruit the cytotoxicactivities of T cells in eradicating tumor cells by recognition of adifferent cell surface antigen, HER2. To this end, we generated andcharacterized bispecific anti-CD3 antibodies having an anti-CD3 arm andan anti-HER2 arm (HER2 TDBs). As described above, the HER2 TDBs wereproduced as full-length antibodies in the knob-into-hole format as humanIgG1, as previously described (Atwell et al. J. Mol. Biol. 270: 26-35,1997). Half antibodies were expressed in either E. coli or Chinesehamster ovary (CHO) cells, purified by Protein A-affinitychromatography, and the proper half antibody pairs were annealed invitro as described previously (Spiess et al. Nat. Biotechnol. 2013). IfTDB antibody production was carried out in CHO cells, the antibodyincluded an aglycosylation mutation, for example, at residue N297 (e.g.,N297G), such that the TDB antibody was an effector-less variant andunable to initiate antibody-dependent cell-mediated cytotoxicity (ADCC).After annealing, the HER2 TDBs were purified by Hydrophobic InteractionChromatography (HIC) and characterized by analytical gel filtration,mass spectrometry, and polyacrylamide gel electrophoresis, as describedabove. One anti-HER2 arm used in the generation of HER2 TDBs was that ofanti-HER2 antibody hu4D5, comprising (a) a VH domain comprising an aminoacid sequence of SEQ ID NO: 270 and (b) a VL domain comprising an aminoacid sequence of SEQ ID NO: 271. Additional HER2 TDBs were generated totarget different regions of the extracellular domain (ECD) of HER2. Ananti-HER2 antibody, 2C4 was used as an anti-Her2 arm comprising (a) a VHdomain comprising an amino acid sequence of SEQ ID NO: 593 and (b) a VLdomain comprising an amino acid sequence of SEQ ID NO: 594. Anotheranti-HER2 antibody used as an anti-HER2 arm was that of anti-HER2antibody, 7C2 comprising (a) a VH domain comprising an amino acidsequence of SEQ ID NO: 595 and (b) a VL domain comprising an amino acidsequence of SEQ ID NO: 596. Other anti-HER2 arms used in the generationof HER2 TDBs included hu4D5 affinity variants, hu4D5.91A and hu4D5.Y100A(described in U.S. Pat. No. 7,435,797).

The specific HER2 TDBs were tested for binding to CD8+ T cells (CD3binding) and SKBR3 cells (Her2 binding), as well as activity, asassessed by in vitro cytotoxicity assays and T cell activation assays.

A. Binding Affinity

Binding affinities for each of the HER2 TDBs were tested by FACSanalysis, as described above for the CD20 TDBs. Briefly, for FACSbinding assays, Jurkat cells (for CD3 antigen), human CD8+ cells (forCD3 antigen), or SKBR3 (for Her2 antigen) were incubated with variousconcentrations of HER2 TDB antibodies at 4° C. for 30 minutes, thencells were washed and incubated with 2^(nd) antibody (anti-huIgG-PE, BDBioscience; or anti-huIgG-AlexaFluor647, Southern Biotech) for another15 minutes, before cells were washed again and ready for FACS analysis.The geo mean of fluorescence was read by flow cytometry. FIGS. 73, 76A,78A-78C, 79A, and 80A-80B show the results of in vitro FACS bindingassays of HER2 TDBs. Multiple HER2 arms that bind to different regionsof HER2 were tested in combination with multiple CD3 arms that bind tovarious regions of CD3ε to characterize the binding properties of eachcombination. FIG. 76A provides the crystal structure of the HER2 ECD andthat of CD3_(ε) and highlights the regions to which the different HER2and CD3 arms bind for each. The hu4D5 HER2 antibody is known astrastuzumab and binds to an epitope in domain IV of HER2 that is theprotein region closest to the cellular membrane. The recombinanthumanized monoclonal antibody 2C4 (rhuMAb 2C4) is also known aspertuzumab that binds to an epitope in domain II of HER2 that is 50Angstroms from where hu4D5 binds. Pertuzumab (PERJETA®, Genentech, Inc,South San Francisco) represents the first in a new class of agents knownas HER dimerization inhibitors (HDI) and functions to inhibit theability of HER2 to form active heterodimers or homodimers with other HERreceptors (such as EGFR/HER1, HER2, HER3 and HER4) (Harari and Yarden.Oncogene 19:6102-6114, 2000; Yarden and Sliwkowski. Nat. Rev. Mol. CellBiol. 2:127-137, 2001; Sliwkowski. Nat. Struct. Biol. 10:158-159, 2003;Cho et al. Nature 421:756-60, 2003; and Malik et al. Pro. Am. Soc.Cancer Res. 44:176-177, 2003). Anti-HER2 murine antibody 7C2 binds to anepitope in domain I of HER2 (PCT Publication No. WO 98/17797) that is100 Angstroms away from the HER2 region bound by hu4D5 (FIG. 76A).

Additionally, the binding affinity of HER2 TDB was tested with multipleanti-CD3 arms. One of the given anti-HER2 arms was combined with highaffinity human CD3 targeting arms such as SP34 and 38E4v1. Other HER2TDB combinations included the low affinity human CD3 targeting arms40G5c or the murine CD3 targeting arm of 2C11. UCHT1v9 for its anti-CD3arm and hu4D5 for its anti-HER2 arm, herein referred to as HER2 TDB(UCHT1v9/hu4D5) or HER2 TDB, was compared to the anti-HER2 antibody,trastuzumab, and the trastuzumab-Fab fragments in a competitiveScatchard assay (Ramirez-Carrozzi et al. Nature Immunology. 12:1159-1166, 2011). In this assay, binding to SKBR-3 was determined bycompetition binding of ¹²⁵I-trastuzumab Fab with trastuzumab,trastuzumab-Fab, or bispecific HER2 TDB. FIG. 74A shows the results ofthe in vitro competitive Scatchard assay of HER2 TDB.

B. In Vitro SKBR3 and MCF7 Target Cell Killing and T Cell ActivationAssays

The HER2 TDB combinations of one of the three anti-HER2 arms (hu4D5,2C4, and 7C2) with either the high affinity 38E4v1 or low affinity 40G5canti-CD3 arm were tested in vitro for their ability to mediate targetcell killing of HER2-expressing SKBR3 or MCF7 cells (FIG. 77 ). The invitro activity the hu4D5 TDBs with either anti-CD3 arm proved to be moreeffective than the 2C4 and 7C2 TDBs in mediating maximal SKBR3 and MCF7cell killing as measured by their EC50 (FIG. 78 ). This killing activitywas also dependent on the CD3 arm utilized. The combination of theanti-CD3 arm 38E4v1 with any one of the anti-HER2 hu4D5, 2C4, or 7C2arms was more efficacious than that of the 40G5c HER2 TDB combinations(FIG. 79 ). Further testing of the 6 HER2 TDB combinations revealed thattheir target cell killing activity is not dependent on the level of HER2expression in target cells. FIG. 80 shows that the HER2 TDBs were notselective for high HER2 expressing SKBR3 target cells over low HER2expressing MCF7 target cells. The activity of the HER2 TDB was insteaddependent on the affinity of the anti-HER2 arm for HER2 (FIG. 81 ). Thelow HER2 affinity TDBs retained activity on low HER2-expressing MCF7cells and were not able to selectively kill HER2 amplified SKBR3 cells(FIG. 82 ).

The HER2 TDBs were also assayed for the specificity of the anti-HER2 armfor their respective HER2 epitopes. The killing activity of thehu4D5-40G5c HER2-TDB was limited when combined with increasingconcentrations of Trastuzumab (hu4D5). However, the efficacy oftrastuzumab is not affected by the combination of the hu4D5 TDB with thehu4D5 antibody (FIG. 83 ). By contrast, target cell killing as mediatedby 2C4-40G5c or 7C2 38E4v1 as blocked by co-administration of thebivalent monospecific antibodies pertuzumab (2C4) or 7C2, respectively(FIG. 83 ). When additional anti-HER2 arms were tested in multipleaffinity assays, all clones demonstrating high or medium HER2 TDBactivity competed with trastuzumab or pertuzumab (FIG. 84 ). Foridentification of candidate TDBs to be assayed in vivo, high (38E4v1,38E4, and SP34) and low (40G5c and 2C11) affinity CD3 arms were testedin vitro with mouse-derived humanized CD3+ T cells in combination withhu4D5, 2C4, and 7C2 anti-HER2 arms (FIGS. 85-86 ). From this assay,three candidate TDBs were selected based on their killing activity forfurther characterization in vivo: hu4D5-SP34, hu4D5-2C11, and 2C4-38E4.The treatment of HER2-expressing tumor-bearing animals with thehu4D5-2C11 HER2 TDB resulted in an increase in CD45+ and CD8+ cells inthe tumor as early as 4 hours post-treatment. Upon further analysis,HER2-TDB treated tumors revealed an increase in IFNγ+ and PD1+CD8+ Tcells as well as an increased presence of T regulatory (Treg) cells(FIG. 87B). The detection of increased immune infiltrates in tumors wasalso correlated with a decrease in the tumor volume of HER2-TDB treatedanimals as compared to vehicle control treatment (FIG. 87A). In FIG.88A, the anti-HER2 arm hu4D5 combined with the low affinity anti-CD3arm, 2C11 or high affinity anti-CD3 arm, SP34, both resulted in tumorregression in transgenic HER2 mice. However, this response was notobserved with the lower affinity 2C4 anti-HER2 arm combined with the38E4 high affinity anti-CD3 arm (FIGS. 88A-88B).

HER2 TDB was also compared to bivalent trastuzumab and trastuzumab-Fabfragments for its ability to directly inhibit SKBR3 proliferation.HER2-expressing SKBR3 target cells were plated in 96-well plates at adensity of 5×10³ cells/well and incubated overnight for cell attachmentbefore treatment with the designated antibody or fragment antibody. Cellproliferation/viability was analyzed after 6 days of treatment byCELLTITERGLO® Luminescent Cell Viability Assay (Promega, Madison, Wis.).The results of this assay are shown in FIG. 74B. Additionally, an invitro cytotoxicity assay was performed with trastuzumab, trastuzumabproduced in E. coli, and HER2 TDB to measure their ability to induce NKcell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC)(Jefferis Trends in Pharmacological sciences. 30: 356-362, 2009; Simmonset al. Journal of Immunological Methods. 263: 133-147, 2002). Antibodiesproduced in E. coli are not glycosylated, which results in impaired FcγRbinding, which is required to mediate ADCC. The cytotoxicity assay wasperformed as in Junttila et al. (Cancer Research. 70: 4481-4489, 2010)with a Cytotoxicity Detection Kit; LDH (Roche, Mannheim, Germany).Briefly, lysed cells were detected by lactate dehydrogenase (LDH)release following 4 hours of treatment with the specified antibody. Theresults are shown in FIG. 74C.

The generated HER2 TDBs were also tested for their ability to supportkilling of HER2-expressing SKBR3 target cells and the activation of thecytotoxic effect of T cells. In vitro cytotoxicity was monitored by flowcytometry. Target cells were labeled with carboxyfluoresceinsuccinimidyl ester (CFSE) according to manufacturer's protocol(Invitrogen, #C34554). The CFSE-labeled target cells and purified CD8+ Tcells from human PBMC were mixed in certain E:T ratio (as indicated infigure legends), with or without TDB for 24 hours. At the end of theincubation, the cells were lifted by trypsin and collected from theplate. The cells were resuspended in equal volume of PBS+2% FBS+1 mMEDTA+propidium iodine (PI). Flow cytometry analysis was done on aFACSCalibur in automation format. The number of live target cells wascounted by gating on CFSE+/PI negative cells. The percentage ofcytotoxicity was calculated as follows: % cytotoxicity (live target cellnumber w/o TDB—live target cell number w/TDB)/(live target cell numberw/o TDB)×100. As depicted in FIG. 75 , HER2 TDB showed robust in vitroSKBR3 target cell killing compared to the HER2 TDB having either hu4D5affinity variant 91A or Y100A as its anti-HER2 arm (EC50 ofhu4D5/UCHT1v9 TDB=0.1 ng/ml; hu4D5.91A/UCHT1v9 TDB=25.5 ng/ml;hu4D5.Y100A/UCHT1v9 TDB=not able to be determined).

Additionally, the binding affinity of anti-HER2 hu4D5 variant (0.4 nM)to the HER2 extracellular domain (ECD) is higher than the HER2 arms 2C4(2.0 nM) and 7C2 (1.7 nM), which is shown in FIG. 76B. Furthermore, FIG.76C shows the hu4D5 HER2-TDB is a more potent mediator of MCF7 targetcell killing than the 2C4 HER2-TDB and the 7C2 HER2-TDB. The kinetics ofthe killing induced by HER2 TDB were additionally assayed. As seen inFIG. 94A, no significant killing activity was detected at 4-12 hours.Robust killing was detected at 24 hours and killing activity increasedover time. As shown in FIGS. 90A-90C and 92C, further comparison ofanti-CD3 arms of the hu4D5 HER2-TDB demonstrated the effectiveness ofthe differing clones in mediating the killing of HER2-expressing SKBR3cells. In particular, two HER2 TDBs, hu4D5/38E4c and hu4D5/40G5c, weresurprisingly as effective or better in mediating target cell killingthan the HER2 TDB hu4D5/SP34 (FIGS. 90B and 90C).

When tested for T cell activation assays, FIG. 89 shows that HER2 TDBwas capable of robustly inducing T cell activity in vitro, compared tothe HER2 TDB having either hu4D5 affinity variant 91A or Y100A as itsanti-HER2 arm. Three anti-CD3 arms (SP34, 38E4c, and 40G5c) of the hu4D5HER2-TDB assayed displayed differing binding affinities for the CD3antigen on human CD8+ T cells, as seen in FIG. 91A. Nonetheless, allthree HER2-TDBs were able to mediate CD8+ T-cell activation (FIG. 91B).Additional analysis of the ability of the 38E4 and 38E4c anti-CD3 armsof the hu4D5 HER2-TDB to mediate CD8+ T cell activation is shown in FIG.92D. The kinetics of the T cell activation induced by HER2 TDB wasfurther assayed. Early signs of T cell activation (CD69) appeared 4hafter HER2 TDB treatment was initiated. However, late activation markers(extracellular CD107a) were detected later at the 24 hour time point(FIG. 94A). Additionally, T cell activation was not detected after 48hours when CD8+ cells were incubated with HER2 TDB or target cells thatdo not express human HER2 (BJAB cells). A robust T cell activation wasseen when HER2+ SKBR3 cells were used as targets accompanied by releaseof cytotoxic granules (FIG. 93A).

We also tested the ability of HER2 TDB to induce killing of BT474 targetcells and activate T cells was assayed for the following five ratios ofeffector CD8+ T cells to target cells: 1:5, 1:2, 1:1, 3:1, and 5:1. Thisexperiment reveals the cytotoxicity measured by LDH release wassignificantly reduced by effector cell titration; however even with anE:T ratio of ≤1:1, a weak LDH signal and robust activation of T cellswas detected (FIG. 94B).

In these assays, target cells and purified CD8+ T cells were mixed inthe presence or absence of TDB and T cell activation was analyzed byflow cytometry. At the end of the incubation, cells were stained withCD8-FITC (BD Bioscience, 555634) CD69-PE (BD Bioscience, 555531) andCD107a-Alexa-Fluor647 (eBioscience, 51-1079). Optionally, cells werestained with CD8-FITC and CD69-PE, where T cell activation was evaluatedby the percentage of CD8+CD69+ in CD8+ cells. Alternatively, aftersurface stained with CD8-FITC and CD69-PE, cells were fixed andpermeabilized with Cytofix/CytoPerm solution (BD Bioscience, 554722) andintracellular stained with anti-granzyme B-Alexa-Fluor647 (BDBioscience, 560212). The T cell activation was evaluated by thepercentage of CD8+CD107a+ cells.

Another measure for T cell-mediated cytotoxicity for HER2 TDB(UCHT1v9/hu4D5) measured is a granule exocytosis assay. FIG. 93B showsthe results for soluble perforin (Cell Sciences), granzyme A andgranzyme B (eBioscience) detected from growth media by ELISA accordingto manufacturer's protocols. In this assay, a control TDB (10 ng/ml),one that shares the same CD3-arm as HER2 TDB but has an irrelevanttarget arm, or HER2 TDB (10 ng/ml) was utilized. The antibodies wereindividually incubated for 18 hours with SKBR3 target cells and effectorperipheral blood mononuclear cells (PBMCs), which were separated fromthe blood of healthy volunteers using lymphocyte separation medium (MPBiomedicals, Solon, Ohio). In vitro cytotoxicity was measured by LDHrelease as described above. A series of apoptotic assays were performedwith HER2 TDB (1 ng/ml), effector PBMCs, and SKBR3 target cells. After24 hours of treatment, granule exocytosis coincided with significantHER2 TDB induced elevation of caspase 3/7 activity (CASPASE-GLO® 3/7assay, Promega), apoptosis (Cell Death Detection ELISA^(plus) assay,Roche) and cytotoxicity as measured by lactate dehydrogenase (LDH)release, which is described above (FIG. 93C).

The ability of HER2 TDB to induce killing of HER2 or vector-transfected3T3 cells was measured by the aforementioned LDH cytotoxicity assay,where no killing of vector-transfected 3T3-cells was detected after 19hours; in contrast, the HER2 transfected 3T3-cells were very efficientlykilled (FIG. 93D). The killing assay was modified to block the HER2 armbinding using trastuzumab Fab (1 μg/ml) or soluble HER2 extracellulardomain (HER2 ECD) (1 μg/ml) and resulted in the efficient inhibition ofthe killing activity after 24 hours (FIG. 93E). To confirm T celldependence of killing, CD3+ cells were depleted from the PBMC using CD3+MicroBeads from Miltenyi (#130-050-101). FIG. 93F shows the depletionresulted in loss of target cell killing activity after 19 hours asassessed by FACS analysis in the presence of HER2 TDB.

HER2 TDB Induces T Cell Proliferation

To investigate whether HER2 TDB induces T cell proliferation, CD8+ Tcells, target cells (SKBR3) and 0.1 μg/ml HER2 TDB were co-cultured,followed by T cell culture in absence of target cells and HER2 TDB.Proliferation of T cells was measured at day 3 by flow cytometry as adilution of CFSE in CD8+/PI− cells with cell divisions. After 3 days,75% of the T cells pulsed with HER2 TDB and target cells had undergone acell division as shown in FIG. 95A. HER2 TDB induced T cell number wasassayed for by labeling purified CD8+ T cells with CFSE according to themanufacturer's protocol (Invitrogen, #C34554). CFSE-labeled CD8+ T cellswere incubated with target cells in the presence or absence of TDB for19 hours. T cells were collected, washed, and cultured for 2-7 days(RPMI+10% FBS). Live CD8+ cell number (CD8+/PI−) and the percentage ofCFSE dim cells was detected by FACS. In FIG. 95B, the cell number didnot increase. Further supplementing the growth media with IL-2 (20ng/ml) provided a survival signal to CD8+ cells, and a robust T cellproliferation was detected in the T cells, but only if they were exposedto both HER2 TDB and target cells (FIG. 95C). Importantly, no bystandereffect on non-target expressing cells was detected in conditions wheremost HER2+ cells in the same culture were killed. HER2 TDB inducedproliferation and polyclonal expansion of T cells, which may be criticalfor amplification of tumor-infiltrating lymphocytes.

HER2 TDB Activity Correlates with the Target Cell HER2 Expression Level

To investigate the relationship between target copy number and TDBactivity, a panel of cancer cell lines with pre-determined number ofHER2-receptors on the cell membrane was selected (Aguilar et al.Oncogene. 18:6050-62, 1999). HER2 protein expression levels in a HER2negative cell line (BJAB LUC), 3 HER2 low cell lines (MDA435, MDA231,MCF7), and 3 HER2 amplified/overexpressing cell lines (MD453, SKBR3,BT474) were detected by Western blot (FIG. 96A). HER2-negative,HER2-low, and HER2-overexpressing cell lines were incubated with HER2TDB and with effector PBMCs at a ratio of E:T 25:1 for 26 hours. At thistimepoint, cytotoxicity was detected using the LDH release assay. FIG.96B shows the HER2 amplified/overexpressing cells were significantlymore sensitive to the TDB mediated killing (p=0.015, t-test) and wereefficiently lysed at femtomolar to low picomolar concentrations(EC50=0.8-3 pM). Cell lines expressing low levels of HER2 weresignificantly less sensitive to HER2 TDB antibody (EC50=33-51 pM). Aslow as <1000 copies of target antigen was sufficient to support T cellkilling.

For the studies performed in FIGS. 96C-96D, the MCF7 cell line or theBJAB cell line was co-targeted with SKBR3 cells in the presence of HER2TDB in the same killing assay. In this assay, MCF7 or BJAB cells werelabeled with CFSE and mixed with SKBR3 and PBMC (E:T 20:1) followed by19 hours treatment with HER2 TDB. Cells were stained with anti-HER2 APCand PI. FIG. 96C shows the percentage of living SKBR3 (HER2 high, PI−)and MCF7 (CFSE+. PI−) cells detected by FACS and normalized tofluorescent beads. No killing of MCF7 cells was detectable at the EC50for SKBR3 killing. The percentage of living SKBR3 (HER2 high, PI−) andBJAB (CFSE+PI−) cells detected by FACS and normalized to fluorescentbeads is shown. No significant killing of BJAB cells was detectable atany HER2 TDB concentration (FIG. 96D).

Very Low Target Occupancy is Sufficient for TDB Activity

Next, the HER2 occupancy at EC50 for HER2 TDB was calculated usingformula [D]/[D]+K_(D) (where the D=drug and K_(D) for HER2 TDB was 5.4nM). HER2 copy number was previously reported (Aguilar et al. Oncogene.18: 6050-6062, 1999). EC50 values were calculated from dose responsedata in FIG. 97B. FIG. 96E shows that in all tested cell lines less than1% target occupancy was sufficient for efficient killing. In the case ofthe high HER2 expressing cell lines, the required occupancy was evenlower (0.01-0.05%). The calculated absolute number of HER2 TDB bound toHER2 at the EC50 was as low as 10-150 in the low expressing cell lines.These results showcase the extreme potency of HER2 TDB and areconsistent with studies of TCR triggering, which suggest as few as 1-25TCRs need to be engaged to trigger T cell responses (Irvine et al.Nature. 419: 845-849, 2002; Purbhoo et al. Nature Immunology. 5:524-530, 2004; Sykulev et al. Immunity. 4: 565-571, 1996). The potencyof HER2 TDB was consistently in the low picomolar to femtomolar range.Furthermore, as few as 10-500 HER2-bound TDBs were sufficient to inducesignificant in vitro cytotoxicity. As few as ˜1000 copies of HER2 on theplasma membrane were sufficient to induce killing. These studies alsodemonstrated a correlation between target expression levels and in vitrosensitivity to HER2 TDB.

HER2 TDB is Efficient in Killing of HER2+ Cancer Cells Refractory toAnti-HER2 Therapies

Next, cell lines that have previously been shown to express high levelsof HER2 but are insensitive to the direct cellular effects oftrastuzumab and lapatinib in vitro were examined (Junttila et al.,Cancer Cell, 15:429-40, 2009; Junttila et al. Breast Cancer Res Treat,2010). For some cell lines, activation of the PI3K pathway due toacquired activating mutations in the PI3K catalytic subunit (KPL4,HCC202) or by PTEN loss (HCC1596) may cause resistance. A panel of sixcell lines (5 breast, 1 lung) was assayed for LDH release as a measureof cytotoxicity in the presence of effector PBMCs at a ratio of 10:1 andHER2 TDB for 19 hours. The EC50 for HER2 TDB mediated killing was in thefemtomolar or low picomolar range (FIG. 97A). Parental and T-DM1resistant BT474-M1 clones were treated with T-DM1 for 3 days. At thistimepoint, cell viability was measured using CELLTITERGLO® (FIG. 97B).Sensitivity of the cell lines to T-DM1 has been previously reported(Junttila et al. Breast Cancer Res Treat. 2010; Lewis Phillips et al.Cancer Research. 68: 9280-9290, 2008). By comparison, parental and T-DM1resistant BT474-M1 clones were treated with HER2 TDB in the presence ofeffectors CD8+ T cells at a ratio of 3:1 for 24 hours. Cytotoxicity wasdetected using FACS assay (FIG. 97C). In addition, HER2 TDB waseffective in killing HER2+ lung cancer cells. Using two independent cellline models KPL4 and BT474, (FIG. 97B-97C), acquired resistance to T-DM1did not affect the sensitivity to HER2 TDB.

Recruitment of T cell killing activity with HER2 TDB is dependent onHER2 expression, but independent of HER2 signaling pathway, whichsuggests that HER2 TDB may be efficient in treatment of tumors that arerefractory to current anti-HER2 therapies. In accordance, datademonstrated equal activity in treatment of multipletrastuzumab/lapatinib resistant cell lines compared to sensitive cells.Resistance in these cells is generated by various mechanisms affectingHER2 pathway. Data presented here suggest that switching to alternativemechanism of action by using HER2 TDB may broadly enable overcomingresistance to antibody-drug conjugates (e.g., T-DM1), targeted smallmolecule inhibitors (e.g., lapatinib) and therapeutic monoclonalantibodies that block the pathway signaling (e.g., trastuzumab).

Pharmacokinetics of HER2 TDB in Rat

To assess the pharmacokinetic (PK) profile of HER2 TDB, Sprague-Dawleyrats were utilized. Animals were separated into the following twogroups: Group 1: HER2 TDB (10 mg/kg, single IV, n=4); Group 2:trastuzumab (10 mg/kg, single IV, n=4). Samples were taken from 4 ratsper group at time points through 35 days post dose. Approximately 0.2 mlof whole blood was collected via the jugular vein (under CO₂/O₂anesthesia). The samples were allowed to clot and centrifuged underrefrigeration (5° C. for 10 minutes at 2000× g) to obtain serum. Serumsamples were assayed for human IgG by ELISA, where Donkey anti-huFccoated to microtiter plate was used to capture the humanized anti HER2antibodies in circulation and goat anti-huFc-HRP (mouse adsorbed) fordetection. PK parameters were determined with a 2-compartment method(Model 7) using WINNONLIN®, version 5.2.1 (Pharsight Corp., MountainView, Calif.). HER2 TDB does not cross react with rat CD3 or rat HER2and displayed a biphasic disposition typical of an IgG1 with a shortdistribution phase and slow elimination phase (FIG. 98 ). Both theclearance and half-life of HER2 TDB were similar to trastuzumab, andwithin expected range of a typical IgG1 in rats.

HER2 TDB Inhibits Tumor Growth In Vivo in Immuno-Compromised Mice

In vivo efficacy of HER2 TDB was tested in NOD-SCID mice, which lackendogenous functional T and B cells and have reduced levels of NK, DC,and macrophage cell types. In this experiment, NOD/SCID mice(NOD.CB17-Prkdcscid/J, Jackson Labs West) were implanted with 0.36 mg,60 day sustained release estrogen pellets (Innovative Research ofAmerica) 1 to 3 days prior to cell inoculation, subcutaneously over theopposite flank of tumor inoculation. On Day 0, 5×10⁶ MCF7-neo/HER2 cellswere injected either alone or together with 10×10⁶ unstimulated humanPBMC from one of two healthy donors (PBMC 1, 2) in HBSS-matrigel in theright 2/3 mammary fat-pad. Inoculated mice were divided into thefollowing five groups: Group 1: Vehicle (control TDB, 0.5 mg/kg, qwk×3,IV, starting on day 0, n=5-10); Group 2: PBMC(1) (PBMC (1)+control TDB,0.5 mg/kg, qwk×3, IV, starting on day 0, n=5-10); Group 3: PBMC (1)+HER2TDB (PBMC (1)+HER2 TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0,n=5-10); Group 4: PBMC(2) (PBMC (2)+control TDB, 0.5 mg/kg, qwk×3, IV,starting on day 0, n=5-10); and Group 5: PBMC (2)+HER2 TDB (PBMC(2)+HER2 TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0, n=5-10). Thefirst treatments were administered 2 hours post-inoculation. Tumorvolumes from individual mice and fitted tumor volumes of treatmentgroups are presented in FIG. 99A, where HER2 TDB prevented growth ofHER2 expressing tumors.

The dependency of HER2 TDB on human PBMCs was further tested in asimilar immune-compromised mouse model. Again, 5×10⁶ MCF7-neo/HER2 cellswere injected either alone or together with 10×10⁶ unstimulated humanPBMC from a healthy donor (PBMC 3) in HBSS-matrigel in the right 2/3mammary fat-pad, and the first treatments were administered 2 hourspost-inoculation. In FIG. 100A, inoculated mice were divided into thefollowing two groups: Group 1: Untreated (n=7); Group 2: HER2 TDB (HER2TDB, 0.5 mg/kg, qwk×3, IV, starting on day 0, n=7). In FIG. 100B,inoculated mice were divided into the following three groups: Group 1:Untreated (n=7); Group 2: PBMC(3) (PBMC (3)+vehicle, 0.5 mg/kg, qwk×3,IV, starting on day 0, n=7); Group 3: PBMC(3)+control TDB(PBMC(3)+control TDB-2C11, 0.5 mg/kg, qwk×3, IV, starting on day 0,n=7). The resulting tumor volume measurements reveal no effect on thetumor growth in control TDB-treated animals.

HER2 TDB Causes Regression of Large Mammary Tumors in huHER2 TransgenicMice

To model the activity of HER2 TDB in immuno-competent mice, humanMMTV-huHER2 transgenic mice were used (Finkle et al. Clinical CancerResearch. 10: 2499-2511; 2004), and a surrogate HER2 TDB comprising amurine IgG2A CD3 reactive antibody clone 2C11 (Leo et al. Proc Natl AcadSci USA. 84: 1374-1378, 1987) was generated to avoid immune responsetowards the TDB. For expression as muIgG2a, equivalent knob-into-holemutations (Atwell et al. J Mol Biol. 270: 26-35, 1997) were introducedinto the Fc region, as well as D265A and N297G (EU numbering) to abolisheffector function. In muIgG2a HER2 TDBs the “knob” arm is murineanti-HER2 hu4D5 and the “hole” is either chimeric anti-murine CD3 2C11(Leo et al. Proc Natl Acad Sci USA. 84: 1374-1378, 1987) (TDB2C11/hu4D5) or mouse anti-hu CD3 SP34 (Pessano et al. The EMBO Journal.4: 337-344, 1985) (TDB SP34/hu4D5). The muIgG2a bispecific antibodieswere expressed in CHO cells and assembled by in vitro assembly.Bispecific antibodies were purified from contaminants by hydrophobicinteraction chromatography (HIC) as described elsewhere (Speiss et al.Nat Biotechnology. 31: 753-758, 2013). The resulting material wasanalyzed for endotoxin levels using an ENDOSAFE® portable test system(Charles River, USA) and when needed, the endotoxin content was reducedby washing the protein with 0.1% TRITON™ X-114. The in vitro activity ofhu4D5/2C11-TDB was similar to human CD3 reactive HER2 TDB (FIG. 101 ).

In FIGS. 99B-99D, MMTV-huHER2 transgenic animals with establishedmammary tumors were divided into the following two groups: Group 1:Vehicle (0.5 mg/kg, qwk×5, IV, starting on day 0, n=7); and Group 2:HER2 TDB (HER2 TDB (2C11/hu4D5), 0.5 mg/kg, qwk×5, IV, starting on day0, n=7). FIG. 99B shows regression was detected in 57% mice and 43% micehad no detectable tumor following treatment. FIG. 99C shows HER2 TDB(2C11/hu4D5) resulted in more than 50% tumor regression, with theexception of one tumor. Responders included tumors that were >1000 mm³at the start of the treatment as observed in FIG. 99D. In a similarexperiment two control TDBs were utilized where one is a CD3-arm controlTDB, one with the murine specific CD3 arm switched to the human specificCD3 arm (HER2 TDB (SP34/hu4D5)), and one is a control TDB, one thatshares the same CD3-arm as HER2 TDB (2C11/hu4D5) but has an irrelevanttarget arm (CTRL TDB-2C11). In FIG. 99E, MMTV-huHER2 transgenic animalswith established mammary tumors were divided into the following twogroups: Group 1: CD3-arm control TDB (HER2 TDB (SP34/hu4D5), 0.5 mg/kg,qwk×5, IV, starting on day 0, n=5); and Group 2: control TDB (controlTDB-2C11, 0.5 mg/kg, qwk×5, IV, starting on day 0, n=5). The growth ofMMTV-huHER2 transgenic tumors was not affected by control TDBs.

The HER2 TDB was further tested for in vivo efficacy in huCD3 transgenicmice. Human CD3ε transgenic mice have been previously described ((huCD3transgenic), de la Hera et al. J Exp Med. 173: 7-17, 1991). In thisstudy, 0.1 million CT26-HER2 cells were injected subcutaneously intohuCD3 transgenic mice. Once the CT26-HER2 tumors were established,animals were divided into the following two groups: Group 1: Vehicle(0.5 mg/kg, qwk×3, IV, starting on day 0, n=7); Group 2: HER2 TDB (HER2TDB (SP34/hu4D5), 0.5 mg/kg, qwk×3, IV, starting on day 0, n=7). HER2TDB inhibited the growth of established tumors, but the effect wastransient and no complete responses were seen (FIG. 99F). The studydemonstrated the potent in vivo activity of HER2 TDB, including dramaticresponses in MMTV-huHER2 transgenic mice.

In a similar experiment, in vivo efficacy of the mouse reactive HER2 TDB(2C11/hu4D5) was tested in Balb/c mice. Again, syngeneic tumors wereestablished in Balb/c mice by injecting 1×10⁵ CT26-HER2 cellssubcutaneously. Tumor-bearing animals were divided into one of thefollowing four groups: Group 1: Vehicle (0.5 mg/kg, qwk×3, IV, startingon day 0, n=10); Group 2: HER2 TDB (HER2 TDB (2C11/hu4D5), 0.5 mg/kg,qwk×3, IV, starting on day 0, n=10); Group 3: control TDB (CTRL TDB(2C11/hu4D5), 0.5 mg/kg, qwk×3, IV, starting on day 0, n=10); and Group4: TDM-1 (TDM-1, 15 mg/kg, qwk×3, IV, starting on day 0, n=10). FIG. 99Gshows that despite incomplete responses, HER2 TDB significantlyprolonged the time to tumor progression (Log-Rank p-value<0.0001). Bycontrast, the control TDB with an irrelevant tumor arm had no effect ontumor growth. In addition, the tumors were insensitive to TDM-1.

HER2 TDB Inhibits Growth of Established Tumors in Immuno-Competent Mice

Human CD3ε transgenic mice (de la Hera et al. J Exp Med. 173: 7-17,1991) were used to model the activity of HER2 TDB in immuno-competentmice. In this experiment, huCD3 transgenic T cells were extracted fromspleens of huCD3 transgenic and BALB/c mice or from the peripheral bloodof healthy human donors. Cells were stained with mouse or human CD8 andeither human CD3 (clone UCHT1) in FIG. 101A or mouse CD3 (clone 2C11) inFIG. 101B. CD8+ cells were detected by flow cytometry. FIG. 101A showshuCD3 transgenic T cells express human CD3 at approximately 50% of thelevel of human T cells, and FIG. 101B shows huCD3 transgenic T cellsexpress murine CD3 at approximately 50% of the level of BALB/c mice.

Next, huCD3 transgenic T cells were assayed for their ability to killhuman HER2 expressing CT26 target cells in vitro. In this study, T cellswere extracted from spleens of huCD3 transgenic mice, BALB/c mice orfrom peripheral blood from healthy human donors. In vitro killingactivity of CT26-HER2 cells was tested using human CD3-specific HER2 TDB(UCHT1v9/hu4D5) in FIG. 102A or mouse CD3-specific HER2 TDB (2C11/hu4D5)in FIG. 102B. Effector T cells were added at a ratio of 20:1 to targetcells in the presence of the designated HER2 TDB for 40 hours. In vitrocytotoxicity was monitored by flow cytometry. Although killing activityof mouse splenic T cells (EC50=2.4 ng/ml) was consistently lowercompared to human peripheral T cells (EC50=0.4 ng/ml), huCD3 transgenicT cells killed human HER2 expressing target cells in vitro as seen inFIG. 102A. The mouse specific HER2 TDB (2C11/hu4D5) induced target cellkilling by T cells from both huCD3 transgenic (EC50=11 ng/ml) and BALB/c(EC50=10 ng/ml) mice as seen in FIG. 102B.

The T cell dependency of the anti-tumor activity of HER2 TDB was furtherassayed in a syngeneic tumor model. As described above, 1×10⁵ CT26-HER2cells were injected subcutaneously into BALB/c mice. Mice withestablished tumors were divided into one of following two groups: Group1: Vehicle (n=10); Group 2: HER2 TDB (SP34/hu4D5) (HER2 TDB(SP34/hu4D5), 0.5 mg/kg, qwx3, IV, n=10). FIG. 103 shows the activity ofHER2 TDB was dependent on T cells, since HER2 TDB had no effect innon-huCD3 transgenic mice. This study demonstrated huCD3 transgenic micecan be used as a novel efficacy model for the huCD3 targeting molecules.

Example 6. Generation and Characterization of Exemplary CD3/LYPD1 TDBs(LYPD1 TDBs)

We also explored the capacity of TDB antibodies to recruit the cytotoxicactivities of T cells in eradicating tumor cells by recognition of adifferent cell surface antigen, LYPD1. To this end, we generated andcharacterized bispecific anti-CD3 antibodies having an anti-CD3 arm andan anti-LYPD1 arm (LYPD1 TDBs). As described above, the LYPD1 TDBs wereproduced as full-length antibodies in the knob-into-hole format as humanIgG1, as previously described (Atwell et al. J. Mol. Biol. 270: 26-35,1997). Half antibodies were expressed in either E. coli or Chinesehamster ovary (CHO) cells, purified by Protein A-affinitychromatography, and the proper half antibody pairs were annealed invitro as described previously (Spiess et al. Nat. Biotechnol. 2013). IfTDB antibody production was carried out in CHO cells, the antibodyincluded an aglycosylation mutation, for example, at residue N297 (e.g.,N297G), such that the TDB antibody was an effector-less variant andunable to initiate antibody-dependent cell-mediated cytotoxicity (ADCC).After annealing, the LYPD1 TDBs were purified by Hydrophobic InteractionChromatography (HIC) and characterized by analytical gel filtration,mass spectrometry, and polyacrylamide gel electrophoresis, as describedabove. The anti-LYPD1 arm used in the generation of LYPD1 TDBs was thatof anti-LYPD1 antibody YWO.49.H6, comprising (a) a VH domain comprisingan amino acid sequence of SEQ ID NO: 272 and (b) a VL domain comprisingan amino acid sequence of SEQ ID NO: 273. The anti-CD3 arms tested inthe generation of LYPD1 TDBs included UCHT1v9, 40G5, SP34, and 38E4v1.

The specific HER2 TDBs were tested for binding to CD8+ T cells (CD3binding), as well as activity, as assessed by in vitro cytotoxicityassays and T cell activation assays.

A. Binding Affinity

Binding affinities for the each of the LYPD1 TDBs were tested FACSanalysis, as described above for the CD20 TDBs. Briefly, for FACSbinding assays, CD8+ T cells were incubated with various concentrationsof LYPD1 TDB antibodies at 4° C. for 30 minutes, then cells were washedand incubated with 2^(nd) antibody (anti-huIgG-PE; BD Bioscience) foranother 15 minutes, before cells were washed again and ready for FACSanalysis. FIG. 104 shows the results of in vitro FACS binding assays ofLYPD1 TDBs. The binding studies showed that LYPD1 TDBs having eitherUCHT1v9 or 38E4v1 as their anti-CD3 arm demonstrated a higher bindingaffinity for result effector cells.

B. In Vitro OVCAR3.Luc Target Cell Killing and T Cell Activation Assays

The generated LYPD1 TDBs were also tested for their ability to supportkilling of LYPD1-expressing OVCAR3.Luc target cells and the activationof the cytotoxic effect of T cells. In vitro cytotoxicity was monitoredby flow cytometry. Target cells were labeled with CFSE according tomanufacturer's protocol (Invitrogen, #C34554). The carboxyfluoresceinsuccinimidyl ester (CFSE)-labeled target cells and purified CD8+ T cellsfrom human PBMC were mixed in a 3:1 ratio, with or without TDB for 48hours. The cells were resuspended in equal volume of PBS+2% FBS+1 mMEDTA+propidium iodine (PI). Flow cytometry analysis was done on aFACSCalibur in automation format. The number of live target cells wascounted by gating on CFSE+/PI negative cells. The percentage ofcytotoxicity was calculated as follows: % cytotoxicity (live target cellnumber w/o TDB—live target cell number w/TDB)/(live target cell numberw/o TDB)×100. As depicted in FIG. 105 , LYPD1 TDBs with UCHT1v9, 38E4v1,or SP34 for their anti-CD3 arm showed robust in vitro OVCAR3.Luc targetcell killing compared to the LYPD1 TDB having 40G5 as its anti-CD3 arm.

When tested for T cell activation assays, FIG. 106 shows that LYPD1 TDBswith 38E4v1, and, to a lesser extent, UCHT1v9 and SP34, for theiranti-CD3 arm were capable of robustly inducing T cell activity in vitro,compared to the LYPD1 TDB having 40G5c as its anti-CD3 arm. In theseassays, target cells and purified CD8+ T cells were mixed in thepresence or absence of TDB and T cell activation was analyzed by flowcytometry. At the end of the incubation, cells were stained withCD8-FITC (BD Bioscience, 555634) CD69-PE (BD Bioscience, 555531) andCD107a-Alexa-Fluor647 (eBioscience, 51-1079). Alternatively, aftersurface stained with CD8-FITC and CD69-PE, cells were fixed andpermeabilized with Cytofix/CytoPerm solution (BD Bioscience, 554722) andintracellular stained with anti-granzyme B-Alexa-Fluor647 (BDBioscience, 560212). The T cell activation was evaluated by thepercentage of CD8+CD69+ and CD8+CD25+ cells.

Other Embodiments

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, the descriptions and examples should not be construed aslimiting the scope of the invention. The disclosures of all patent andscientific literature cited herein are expressly incorporated in theirentirety by reference.

What is claimed is:
 1. A method of treating or delaying progression of aHER2-positive cancer in a subject, the method comprising administeringto the subject an effective amount of a bispecific antibody that bindsto HER2 and CD3, wherein the bispecific antibody comprises (a) ananti-HER2 arm comprising a first binding domain, the first bindingdomain comprising: a hypervariable region (HVR)-H1 comprising the aminoacid sequence of SEQ ID NO: 169, an HVR-H2 comprising the amino acidsequence of SEQ ID NO: 170, an HVR-H3 comprising the amino acid sequenceof SEQ ID NO: 171, an HVR-L1 comprising the amino acid sequence of SEQID NO: 172, an HVR-L2 comprising the amino acid sequence of SEQ ID NO:173, and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174;and (b) an anti-CD3 arm comprising a second binding domain, the secondbinding domain comprising: an HVR-H1 comprising the amino acid sequenceof SEQ ID NO: 1, an HVR-H2 comprising the amino acid sequence of SEQ IDNO: 2, an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3, anHVR-L1 comprising the amino acid sequence of SEQ ID NO: 4, an HVR-L2comprising the amino acid sequence of SEQ ID NO: 5, and an HVR-L3comprising the amino acid sequence of SEQ ID NO:
 6. 2. The method ofclaim 1, wherein the first binding domain comprises: (a) a heavy chainvariable (VH) domain comprising an amino acid sequence having at least95% sequence identity to the amino acid sequence of SEQ ID NO: 270; (b)a light chain variable (VL) domain comprising an amino acid sequencehaving at least 95% sequence identity to the amino acid sequence of SEQID NO: 271; or (c) a VH domain as in (a) and a VL domain as in (b); andthe second binding domain comprises: (a) a VH domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 184; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 185; or (c) a VH domain as in (a) and a VL domainas in (b).
 3. The method of claim 1, wherein the second binding domainbinds to a human CD3ε polypeptide or a cynomolgus monkey (cyno) CD3εpolypeptide.
 4. The method of claim 1, wherein the bispecific antibodycomprises a substitution mutation in the Fc region that reduces effectorfunction.
 5. The method of claim 4, wherein the substitution mutation isan aglycosylation site mutation.
 6. The method of claim 5, wherein theaglycosylation site mutation is at amino acid residue N297, L234, L235,and/or D265 (EU numbering).
 7. The method of claim 6, wherein theaglycosylation site mutation is selected from the group consisting ofN297G, N297A, L234A, L235A, and D265A.
 8. The method of claim 1, whereinthe bispecific antibody is monoclonal, humanized, or chimeric.
 9. Themethod of claim 8, wherein the bispecific antibody is an antibodyfragment that binds HER2 and CD3.
 10. The method of claim 9, wherein theantibody fragment is a Fab, Fab′-SH, Fv, scFv, or (Fab′)₂ fragment. 11.The method of claim 8, wherein the bispecific antibody is a full-lengthantibody.
 12. The method of claim 1, wherein the HER2-positive cancer isa HER2-positive breast cancer or a HER2-positive gastric cancer.
 13. Themethod of claim 1, further comprising administering to the subject aPD-1 axis binding antagonist and/or an additional therapeutic agent. 14.The method of claim 13, wherein the PD-1 axis binding antagonist and/oradditional therapeutic agent is administered prior to, or concurrentlywith, the administration of the bispecific antibody.
 15. The method ofclaim 13, wherein the PD-1 axis binding antagonist and/or additionaltherapeutic agent is administered subsequent to the administration ofthe bispecific antibody.
 16. The method of claim 13, wherein the PD-1axis binding antagonist is a PD-L1 binding antagonist, a PD-1 bindingantagonist, or a PD-L2 binding antagonist.
 17. The method of claim 16,wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist,and wherein the PD-L1 binding antagonist is MPDL3280A, MDX-1105, orMED14736.
 18. The method of claim 17, wherein the PD-L1 bindingantagonist is MPDL3280A.
 19. The method of claim 16, wherein the PD-1axis binding antagonist is a PD-1 binding antagonist, and wherein thePD-1 binding antagonist is MDX-1106 (nivolumab), MK-3475(lambrolizumab), or AMP-224.
 20. The method of claim 16, wherein thePD-1 axis binding antagonist is a PD-L2 binding antagonist, and whereinthe PD-L2 binding antagonist is an antibody or an immunoadhesin.
 21. Themethod of claim 1, further comprising administering to the subject aglucocorticoid or an antibody-drug conjugate (ADC).
 22. The method ofclaim 1, wherein the bispecific antibody is administered to the subjectin a dosage of about 0.01 mg/kg to about 10 mg/kg.
 23. The method ofclaim 1, wherein the bispecific antibody is administered intravenously,subcutaneously, intramuscularly, topically, orally, transdermally,intraperitoneally, intraorbitally, by implantation, by inhalation,intrathecally, intraventricularly, or intranasally.
 24. The method ofclaim 23, wherein the bispecific antibody is administered intravenously.25. A method of enhancing immune function in a subject having aHER2-positive cancer, the method comprising administering to the subjectan effective amount of a bispecific antibody that binds to HER2 and CD3,wherein the bispecific antibody comprises (a) an anti-HER2 armcomprising a first binding domain, the first binding domain comprising:an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169, anHVR-H2 comprising the amino acid sequence of SEQ ID NO: 170, an HVR-H3comprising the amino acid sequence of SEQ ID NO: 171, an HVR-L1comprising the amino acid sequence of SEQ ID NO: 172, an HVR-L2comprising the amino acid sequence of SEQ ID NO: 173, and an HVR-L3comprising the amino acid sequence of SEQ ID NO: 174; and (b) ananti-CD3 arm comprising a second binding domain, the second bindingdomain comprising: an HVR-H1 comprising the amino acid sequence of SEQID NO: 1, an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2,an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3, an HVR-L1comprising the amino acid sequence of SEQ ID NO: 4, an HVR-L2 comprisingthe amino acid sequence of SEQ ID NO: 5, and an HVR-L3 comprising theamino acid sequence of SEQ ID NO:
 6. 26. The method of claim 25, whereinthe first binding domain comprises: (a) a VH domain comprising an aminoacid sequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 270; (b) a VL domain comprising an amino acidsequence having at least 95% sequence identity to the amino acidsequence of SEQ ID NO: 271; or (c) a VH domain as in (a) and a VL domainas in (b); and the second binding domain comprises: (a) a VH domaincomprising an amino acid sequence having at least 95% sequence identityto the amino acid sequence of SEQ ID NO: 184; (b) a VL domain comprisingan amino acid sequence having at least 95% sequence identity to theamino acid sequence of SEQ ID NO: 185; or (c) a VH domain as in (a) anda VL domain as in (b).
 27. The method of claim 25, wherein the secondbinding domain binds to a human CD3ε polypeptide or a cyno CD3εpolypeptide.
 28. The method of claim 25, wherein the bispecific antibodycomprises a substitution mutation in the Fc region that reduces effectorfunction.
 29. The method of claim 28, wherein the substitution mutationis an aglycosylation site mutation.
 30. The method of claim 29, whereinthe aglycosylation site mutation is at amino acid residue N297, L234,L235, and/or D265 (EU numbering).
 31. The method of claim 30, whereinthe aglycosylation site mutation is selected from the group consistingof N297G, N297A, L234A, L235A, and D265A.
 32. The method of claim 25,wherein the bispecific antibody is monoclonal, humanized, or chimeric.33. The method of claim 32, wherein the bispecific antibody is anantibody fragment that binds HER2 and CD3.
 34. The method of claim 33,wherein the antibody fragment is a Fab, Fab′-SH, Fv, scFv, or (Fab′)₂fragment.
 35. The method of claim 32, wherein the bispecific antibody isa full-length antibody.
 36. The method of claim 25, wherein theHER2-positive cancer is a HER2-positive breast cancer or a HER2-positivegastric cancer.
 37. The method of claim 25, further comprisingadministering to the subject a PD-1 axis binding antagonist and/or anadditional therapeutic agent.
 38. The method of claim 37, wherein thePD-1 axis binding antagonist and/or additional therapeutic agent isadministered prior to, or concurrently with, the administration of thebispecific antibody.
 39. The method of claim 37, wherein the PD-1 axisbinding antagonist and/or additional therapeutic agent is administeredsubsequent to the administration of the bispecific antibody.
 40. Themethod of claim 37, wherein the PD-1 axis binding antagonist is a PD-L1binding antagonist, a PD-1 binding antagonist, or a PD-L2 bindingantagonist.
 41. The method of claim 40, wherein the PD-1 axis bindingantagonist is a PD-L1 binding antagonist, wherein the PD-L1 bindingantagonist is MPDL3280A, MDX-1105, or MED14736.
 42. The method of claim41, wherein the PD-L1 binding antagonist is MPDL3280A.
 43. The method ofclaim 40, wherein the PD-1 axis binding antagonist is a PD-1 bindingantagonist, wherein the PD-1 binding antagonist is MDX-1106 (nivolumab),MK-3475 (lambrolizumab), or AMP-224.
 44. The method of claim 42, whereinthe PD-1 axis binding antagonist is a PD-L2 binding antagonist, whereinthe PD-L2 binding antagonist is an antibody or an immunoadhesin.
 45. Themethod of claim 25, further comprising administering to the subject aglucocorticoid or an ADC.
 46. The method of claim 25, wherein thebispecific antibody is administered to the subject in a dosage of about0.01 mg/kg to about 10 mg/kg.
 47. The method of claim 25, wherein thebispecific antibody is administered intravenously, subcutaneously,intramuscularly, topically, orally, transdermally, intraperitoneally,intraorbitally, by implantation, by inhalation, intrathecally,intraventricularly, or intranasally.
 48. The method of claim 47, whereinthe bispecific antibody is administered intravenously.
 49. The method ofclaim 1, further comprising administering to the subject one or moreadditional therapeutic agents that target the HER pathway.
 50. Themethod of claim 49, wherein the one or more additional therapeuticagents that target the HER pathway is selected from trastuzumab, T-DM1,and pertuzumab.
 51. The method of claim 50, wherein the one or moreadditional therapeutic agents that target the HER pathway istrastuzumab.
 52. The method of claim 25, further comprisingadministering to the subject one or more additional therapeutic agentsthat target the HER pathway.
 53. The method of claim 52, wherein the oneor more additional therapeutic agents that target the HER pathway isselected from trastuzumab, T-DM1, or pertuzumab.
 54. The method of claim53, wherein the one or more additional therapeutic agents that targetthe HER pathway is trastuzumab.
 55. The method of claim 2, wherein thefirst binding domain comprises: a VH domain comprising the amino acidsequence of SEQ ID NO: 270 and a VL domain comprising the amino acidsequence of SEQ ID NO: 271; and the second binding domain comprises: aVH domain comprising the amino acid sequence of SEQ ID NO: 184 and a VLdomain comprising the amino acid sequence of SEQ ID NO:
 185. 56. Themethod of claim 26, wherein the first binding domain comprises: a VHdomain comprising the amino acid sequence of SEQ ID NO: 270 and a VLdomain comprising the amino acid sequence of SEQ ID NO: 271; and thesecond binding domain comprises: a VH domain comprising the amino acidsequence of SEQ ID NO: 184 and a VL domain comprising the amino acidsequence of SEQ ID NO: 185.